BR112016017999B1 - TABLET AND FORMULATION SUITABLE FOR Squeezing INTO A TABLET - Google Patents

Abstract

TABLET AND FORMULATION SUITABLE FOR PRESSING INTO A TABLET The present invention is directed to compositions comprising an extrudate or solid solution of a compound, or a salt thereof, of Formula I (API): Formula I, wherein "Ra" is independently -H or -F, in a water-soluble polymeric matrix which also comprises a disintegration system enabling a tablet manufactured therefrom to rapidly disintegrate in the environment in which the API is to be released.

Description

FUNDAMENTALS OF THE INVENTION

[001] CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by altered tissue-specific processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system. Calcitonin Gene-Related Peptide (CGRP) is a potent vasodilator neurotransmitter believed to play a key role in the pathophysiology of migraine. Initial human clinical validation of targeted CGRP was provided by Boehringer Ingelheim in 2003 with the report that an IV formulation comprising olcegepant was effective in the acute treatment of migraine and the mechanism was confirmed by a study using telcagepant (a CGRP antagonist) in a oral formulation.

[002] Recently developed CGRP antagonist compounds are described in the published international application, publication No. WO 2012/064910, which are based on the structure of FORMULA I: , Formula I, where “Ra” are various substituents (for example, where “Ra” is hydrogen: (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1 -(2,2,2-trifluoroethyl)-piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridin-6,3'-pyrrol[ 2,3-b]pyridine]-3-carboxamide and, for example, where three of "Ra" are selected to be fluorine: (S)-N-((3S,5S,6R)-6-methyl-2-oxo -1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro- [cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide). These compounds offer hope as potent, well-tolerated CGRP antagonists with low potential for side effects and metabolic complications. However, these compounds have low solubility and, in general, do not form salts suitable for the preparation of a stable pharmaceutical formulation.

[003] For initial in vivo study, it is common to administer poorly soluble “class II” compounds formulated as a liquid formulation, for example, as a co-solvent or lipid-based solution using a co-solvent such as PEG400, and other constituents such as necessary to facilitate dissolution and enhance oral absorption. While useful for clinical studies, it is generally not commercially attractive to provide a liquid formulation for the oral delivery of medications for use in therapy for acute or chronic conditions or for use in the prophylactic treatment of chronic conditions. Desirably, such drugs should be in solid form for oral administration, for example, a compressed tablet or capsule containing the API. In general, however, drugs with low aqueous solubility are difficult to release into the gastrointestinal system without some solubility enhancer or permeation enhancer, or both, present at the site of absorption.

[004] Solid dispersions, and particularly solid solutions, have been used to promote oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs), see, for example, Ford, Pharm Acta Helv, 1986, 61: 69 -88. Solid dispersions and solid solutions are compositions in which the API is dispersed in or dissolved in a solid matrix, usually a polymeric matrix. Solid solutions and solid dispersions (where the active pharmaceutical ingredient forms a homogeneous or nearly homogeneous glass in the excipient matrix) are of particular interest in the oral delivery of poorly water soluble compounds. These materials are believed to enhance the absorption of orally administered API by improving: (i) the wetting properties of the API; (ii) causing at the point of transient absorption to supersaturate the API with respect to a lower energy phase API (eg crystalline); or (iii) both effects. In general, solid solutions are believed to be capable of drug absorption by increasing the rate of dissolution and/or the degree to which the drug is dissolved from the matrix.

[005] An example of a class II drug that has been formulated as a solid solution is posaconazole, as described in International Patent Application, Publication No. WO2009/129300, published October 22, 2009. Such posaconazole compositions were prepared by forming Posaconazole was extruded into polymer derivatized hydroxypropylmethyl cellulose acetate succinate (HPMCAS), which solid dispersion was subsequently blended with microcrystalline cellulose, additional HPMC-AS, hydroxypropylcellulose, and magnesium stearate. This blend was compressed to provide an orally bioavailable posaconazole formulation with desirable PK and bioavailability.

[006] Other examples of polymers used in providing a solid solution polymer and API is reported by Goertz et al. In U.S. Pat. No. 4,801,460 which describes solid dispersions comprising a sparingly soluble drug (exemplified by theophylline) and a polyvinylpyrrolidone/vinyl acetate cross-linked copolymer (PVP copolymer). The '460 patent discloses drug release times of up to 8 hours in tests, and does not disclose instant release drugs using such polymer matrix solid solutions.

[007] In another example, in International Published Application No. WO98/029137 (the '137 publication), published on July 9, 1998, Takagi et al. describes compositions comprising an API dissolved in a matrix comprising a cellulosic polymer, e.g. hydroxypropylmethyl-, hydroxyethyl- and hydroxypropyl-cellulose, and salts having an endothermic heating of dissolution, e.g. sodium bicarbonate, which is said to improve the disintegration rate. The '137 publication identifies the compositions taught herein as being similar to mixtures utilizing a carbonate or bicarbonate salt in the presence of a solid, water-soluble acid which aids in disintegration when exposed to an aqueous environment via the effervescent action.

[008] In another example, Fry et al. describe formulations of HER-2 inhibitors dispersed in a wide variety of polymeric matrices, including many different derivatives of cellulosic polymers (including graft copolymers that incorporate cellulosic moieties), vinyl alcohol polymers, and polyvinylpyrrolidine polymers. See International Published Application Publication No. WO2013/056108, published April 18, 2013. Such compositions are said to reduce interpatient PK variability.

[009] Despite their increasing use, the design of solid solution formulations to effectively promote oral drug absorption remains largely a matter of trial and error. The successful formulation of lipophilic compounds as solid dispersions to promote oral absorption can benefit from a strong interaction between the API and polymer. This has led to interest in partially water-soluble polymers with amphiphilic properties such as hydroxypropyl methylcellulose acetate succinate (HPMCAS), especially when the process used to create the solid dispersion is spray drying. See, Friesen et al., Mol. Pharm., 2008, 5:1003-1019. While this method has been successful for many drug candidates, it has been suggested that compounds with high melting points (or high melting point to glass transition temperature ratios) and/or particularly lipophilic compounds (e.g., those with high log P) are especially problematic for successfully formulating solid solutions. Friesen et al. suggests that successful formulations of compounds having high melting point properties will likely be limited to relatively dilute concentrations of API in the solid dispersion.

[0010] As will be appreciated from the foregoing, while it is desirable to provide compounds of FORMULA I in solid form for oral dosage administered via the gastrointestinal tract, the nature of the therapy provided requires that the drug render the compound of the FORMULA I immediately available to the patient to whom it is being administered. There is a shortage of immediate release formulations disclosed at the present time based on dispersions or solid solutions of a class II API in a polymeric matrix.

SUMMARY OF THE INVENTION

[0011] In one aspect, the present invention provides a tablet comprising: (a) an extrudate comprising: (i) a water-soluble polymeric matrix; (ii) a dispersing agent; and (iii) a compound of FORMULA I, or a pharmaceutically acceptable salt thereof: Formula I, wherein "Ra" is independently -H or -F, and wherein the dispersing agent and compound of FORMULA I are dispersed within said polymeric matrix; and (b) a disintegration system, wherein said tablet has a hardness of about 12 kP to about 18 kP, and wherein said tablet achieves complete disintegration in less than about 5 minutes in a temperature test. standard tablet disintegration in accordance with USP 31-NF26 Chapter 701 using aqueous HCl (pH 1.8) at 37°C.

[0012] In some embodiments it is preferred that the water-soluble polymeric matrix of said extrudate is a polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA) matrix.

[0013] In some embodiments, it is preferred for the disintegration system to comprise sodium chloride powder and croscamellose sodium, and more preferably in a 1:1 ratio by weight.

[0014] In some embodiments, it is preferred for a tablet to have a hardness of about 12 kP to about 16 kP. In some embodiments, it is preferred for the tablet to have a tensile strength of about 1.75 MPa.

[0015] In some embodiments, it is preferred that a tablet of the invention release at least about 90% by weight of the compound of Formula I contained therein when subjected to a dissolution test in accordance with USP 30 NF25 Chapter 711, Device #2 equipped with USP 2 paddles, operated at 50 rpm, in 900 ml of simulated gastric fluid (pH 1.8) at 37°C.

[0016] In some embodiments, preferably the tablet comprises a disintegration system comprising: (a) powdered sodium chloride, wherein said sodium chloride is characterized by: (i) a d50 value of less than about 210 microns; (ii) a d10 value of less than about 50 microns; and (iii) a d90 value of less than about 470 microns; and (b) croscarmellose sodium, wherein said powdered sodium chloride and said croscarmellose sodium are present in a 1:1 weight ratio, and wherein the amount of extrudate present in the tablet is selected to provide from about 9% by weight to about 10% by weight of the compound of Formula I in this dispersion.

[0017] In some embodiments, it is preferred for the disintegration system to comprise about 20% by weight of the tablet. In some embodiments, the tablet comprises about 50% extrudate by weight.

[0018] In some embodiments, the liquid tabletting formulation of the invention comprises (i) the extrudate; (ii) the disintegration system; (iii) one or more diluents, in some embodiments it is preferred to select mannitol and microcrystalline cellulose as diluents; (iv) a glidant, in some embodiments it is preferred to use colloidal silica as a glidant; and (v), and one or more lubricants, in some embodiments it is preferred to use sodium stearyl fumarate as a lubricant.

[0019] In some embodiments, it is preferred that the compound of FORMULA I is a compound of FORMULA IA, or a salt thereof: Formula Ia, where each of "Rb" is -H or each of "Rb" is -F.

[0020] In some embodiments, preferably the water-soluble polymeric matrix of said extrudate is a water-soluble polyvinylpyrrolidone/vinyl acetate copolymer, preferably a polyvinylpyrrolidone/vinyl acetate copolymer made from a free radical polymerization of a 6:4 ratio of vinylpyrrolidone monomer:vinyl acetate.

[0021] In some embodiments where the FORMULA I compound is a FORMULA IA compound, preferably, the FORMULA IA compound is present in the extrudate from about 20% by weight of the extrudate to about 22% by weight of the extrudate .

[0022] In some embodiments, preferably the extrudate comprises -tocepherol polyethylene glycolsuccinate (TPGS) as a dispersing agent, which is present in an amount comprising at least about 5% by weight of the finished extrudate.

[0023] In some embodiments, the extrudate preferably comprises a soluble polyvinylpyrrolidone/vinyl acetate copolymer that is present in an amount comprising from about 50% by weight of the extrudate to about 80% by weight of the extrudate, preferably from about 70% by weight of the extrudate to about 75% by weight of the extrudate.

[0024] In one aspect, the invention provides a formulation suitable for providing a compressed tablet, the formulation comprising: a) an extruded composition comprising a water-soluble polyvinylpyrrolidone/vinyl acetate copolymer matrix (PVP-VA copolymer) and dispersed in this: (1) an active compound of FORMULA IA, or a pharmaceutically acceptable salt thereof: Formula IA, wherein all Rb are either -H or all Rb are -F; and polyethylene glycol tocopheryl succinate (TPGS), wherein said FORMULA IA compound comprises from about 5% by weight to about 23% by weight of said extrudate and TPGS comprises at least about 5% by weight of said extrudate ; and b) a disintegration system comprising: (i) croscarmellose sodium; and (ii) powdered sodium chloride, wherein said disintegration system comprises about 20% by weight of said formulation, and wherein said formulation is also characterized by providing a tablet having a hardness of about 12 kP up to about 18 kP, preferably from about 12 kP to about 16 kP, which tablet when subjected to a dissolution test in accordance with USP 30 NF25 Chapter 711, in a paddle stirring device equipped with USP 2 paddles, operated at 50 rpm in 900 ml of simulated gastric fluid (pH 1.8) at 37°C releases at least about 90% of the Formula Ia compound contained therein in less than about 20 minutes.

[0025] In some embodiments a tablet formulation of the invention comprises in addition to the extrudate and disintegration system: (i) mannitol, preferably about 20% by weight of the formulation; (ii) microcrystalline cellulose, preferably up to about 20% by weight of the formulation; (iii) colloidal silica, preferably about 0.25% by weight of the formulation; and (iv) sodium stearyl fumarate, preferably about 0.75% by weight of the formulation. In some embodiments, preferably the tablet formulation comprises about 50% by weight of said extrudate.

BRIEF DESCRIPTION OF THE FIGURES

[0026] FIG 1: Flow Chart Illustrating Unit Operations of the General Preparation of Dispersion of the Invention

[0027] FIG. 2: Flowchart Illustrating Unit Operations in Alternative General Preparation of Invention Dispersion

[0028] FIG. 3: Flowchart Illustrating Unit Operations in Formulation Tablets of the Invention.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The following terminology, which may be used herein, is used in accordance with the following definitions.

[0030] Unless expressly stated otherwise, all ranges quoted herein are inclusive; that is, the range includes the values for the upper and lower limits of the range, as well as all values in between. As an example, the temperature ranges, percentages, equivalent ranges, and the like described herein include the upper and lower limits of the range and any continuous value therebetween.

[0031] The term "formulation", as used herein, refers to a mixture, aggregation, solution or other combination of materials that includes an active pharmaceutical ingredient (API) whose formulation is adapted to a particular mode of administration, for example, a formulation suitable for pressing into tablets designed for oral administration, in treatment, administration, prevention and so on. of a disease state or condition in a patient.

[0032] The term "patient" as used herein refers to an animal, preferably a mammal, most preferably a human being, who has been the object of treatment, observation or experiment. When a human patient suffering from the condition being treated is included in the activity, they are alternatively referred to here as a “patient”.

[0033] As mentioned above, the present invention is directed to an extruded (extruded) composition comprising a soluble polymeric matrix and dispersed or dissolved therein, a compound of Formula I, or a pharmaceutically acceptable salt thereof: Formula I, wherein "Ra" is independently -H or -F, and a dispersing agent, for example vitamin E polyethylene glycol succinate (TPGS), which extrudate is incorporated into a pharmaceutical formulation comprising a disintegration system, which formulation it is suitable for providing tablets of up to 18 kP, in some embodiments preferably 16 kP, hardness that will disintegrate within about 5 minutes in standard disintegration tests.

[0034] The compound of FORMULA I suitable for use in the compositions of the invention can be prepared according to the synthesis described in WO 2012/064910. In some embodiments it is preferable to crystallize the crude compound of FORMULA I prepared in accordance with the foregoing from an ethanol/water solvent, thereby providing a crystalline trihydrate form of the compound, and to grind the crystalline material to a particle size that provides a free flowing powder that can be fed into the extruder equipment used in preparing the dispersion. As will be appreciated, where noted, the weight ratios and weight percentages described for the compound of Formula I in the formulations and tablets described herein are adjusted to reflect the weight of an equivalent amount of 100% active free base of the compound without the solvent of crystallization or inert material as would be taken into account when preparing the formulation using materials having activity of less than 100%.

[0035] With reference to Figures 1 and 2, in general, the extrudate is prepared by hot melt extrusion (HME) of a compound of FORMULA I and various excipients which may or may not have received additional operations to make them suitable for HME processing.

[0036] The inventors have surprisingly discovered that, contrary to common experience with Class II pharmaceutical compounds which are often dispersed in many different polymers, as disclosed above, FORMULA I compounds tend to thermally degrade when attempts are made to incorporate them. them into a matrix comprising some commercially available cellulosic polymers using HME techniques. For example, using HPMCAS as the polymeric matrix leads to the formation of excessive degradation products in the dispersion produced. In some experiments, using a cellulosic polymer as the dispersion matrix to prepare dispersions of the FORMULA I compound by HME resulted in up to 25 times the amount of API degradation than subjecting the API alone to the same thermal excursion generated.

[0037] Surprisingly, the inventors discovered that one type of commercially available polymeric material from which a dispersion of the compound of FORMULA I could be prepared without exacerbating the thermal degradation of the compound were commercially available water-soluble polymers, e.g. of polyvinylpyrrolidone/vinyl acetate (PVP-VA polymers). It was surprisingly found that dispersions prepared by the HME technique using a water-soluble polymer, for example a PVP-VA polymer and a FORMULA I compound did not result in any greater thermal degradation than subjecting the crude FORMULA I compound alone to the same thermal tour. Therefore, intimate mixtures of the "FIA-H" free base compound (the FORMULA IA compound where all the "Rb's" are -H,) or the "FIA-F" free base compound (the FORMULA IA compound where all "Rb" are -F) and one of the two potential matrix polymers were subjected to 2 minutes heating at 170°C in a TGA instrument stage, then cooled to room temperature and spectroscopically damaged for formation of known thermal degradation products. These data are summarized in Table I. TABLE I

[0038] As illustrated in Table I, these data indicate that some commercially available cellulosic polymers exacerbate the thermal degradation of both FIA-H and FIA-F compounds

[0039] Furthermore, the inventors have discovered that typically HME processing temperatures can reach 180°C, which results in an even higher percentage of loss of a FORMULA I compound to degradation products. Thus, investigators have surprisingly discovered that dispersing FORMULA I compounds into soluble polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA copolymer) copolymers using a hot melt processing (HME) technique operates with the same thermal excursions used when a cellulosic polymer was used, resulted in a redaction of the degradation products detected in the extruded product. Typically, the percentage degradation product increase observed in such an extrudate was not greater than the percentage degradation product increase observed when samples of the same FORMULA I compound were subjected to the same thermal excursion experienced in the HME process.

[0040] In accordance with the foregoing, suitable water-soluble polymers for use in the compositions of the invention are any soluble PVP-VA copolymer that is manufactured by free radical polymerization of a 6:4 ratio of vinylpyrrolidone monomer: vinyl acetate. An example of commercially available copolymers of this type is the polyvinylpyrrolidone/vinyl acetate copolymer sold under the tradename Kollidon® 64, and equivalents thereof.

[0041] In addition to a polymeric matrix and at least one compound of FORMULA I, an extrudate of the invention will include some amount of an excipient which acts as a dispersing agent. As the term is used herein a dispersing agent can reduce the thermal energy required to drive the FORMULA I compound into solution in the polymeric matrix and promote dispersion formation with even lower degradation losses in the FORMULA I compound dispersed in the matrix. For the extrudates of the invention, in some embodiments, it is preferred to use vitamin E in the form of its polyethylene glycol succinate (d-alpha-tocopheryl polyethylene glycol succinate, or TPGS, contained herein). An example of a commercially available TPGS suitable for use in extrudates of the invention is one that provides d-alpha-tocopheryl succinate esterified with polyethylene glycol 1000, for example, but not limited to, Vitamin E d-TPGS NF from Eastman Chemical Company . In some embodiments, preferably the TPGS is used as the dispersing agent and is present in the finished extrudate in an amount that is at least about 5% by weight of the extruded composition.

[0042] It will be appreciated that other dispersing agents, for example polyethoxylated castor oil (eg cremophor) may also be used.

[0043] The relative amount of the compound of FORMULA I, polymeric matrix and dispersing agent used in the compositions of the invention, expressed as % by weight of the extruded (extruded) compositions, can vary and still be within the scope of the invention. Typically, the matrix polymer is present in an amount adjusting the balance of the composition after subtracting 0% by weight of the API and dispersing agent. Typically, the amount of matrix polymer is about 70% by weight to 75% by weight of the finished extrudate. In some embodiments, compositions of the invention are preferred which include an amount of the FORMULA I compound which, corrected for its relative activity compared to 100% pure free base compound of FORMULA I, is equivalent to no more than 25% by weight of 100% free base compound contained within the finished extruded composition. In some embodiments, preferably, the amount of the FORMULA I compound present in the finished extrudate is equivalent in activity from about 5% by weight to about 22% by weight of 100% pure free base compound in the finished extrudate, and most preferably an amount equivalent in activity to at least about 20% by weight of the 100% free base compound in the finished extrudate.

[0044] The compositions of the invention can be prepared by processes that are suitable for causing the selected API (e.g., a compound of FORMULA IA) to form a dispersion throughout the polymeric matrix such that the drug is generally a uniform dispersion amorphous in the polymer or dissolved in the polymer. In general, this requires some method of heating and mixing the constituents of the desired composition together and recovering the dispersion or solution in a solid form. While it will be appreciated that any means of producing a dispersion can be used without departing from the invention, in some embodiments, it is preferred to prepare the compositions of the invention via Hot Melt Extrusion (HME). Hot melt extrusion (HME) is a technique in which an extruder, for example a 27 mm Leistritz twin screw extruder, is used to mix and heat the polymer, drug, and dispersing agent, while forming the dispersion or finished compounding solution in a "noodle" or other conveniently handled form that can be used in further processing in the preparation of tabletting (extruded) formulations.

[0045] In carrying out such operations, some or all of the components may be pre-mixed before introducing them into the extruder, for example by mixing dry powders or dry grinding or dry mixing, the constituents together in a stirring process , mixing or granulating to ensure intimately mixed constituents leading to a homogeneous mixture of constituents when the mixture is fed into the extruder. Alternatively, the constituents can be fed into the extruder using independent feed streams (see Polymer Extrusion 4th Edition by Chris Rauwendaal 2001, Hanser Gardner Publications, Inc., Cincinnati, OH or Schenck et al., (2010), Achieving a Hot Melt Extrusion Design Space for the Production of Solid Solutions, in Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing (ed. D. J. am Ende), John Wiley & Sons, Inc., Hoboken, NJ, USA). While for some compositions of the invention it is preferred to use an HME process to be prepared, it will be appreciated that the compositions of the invention may be prepared by any means useful for preparing a melt in any convenient device in which a mixture of a compound of FORMULA I, matrix polymer and dispersing agent can be heated, mixed and recovered.

[0046] In general, when subjecting materials to extrusion, the act of conveying the material through the extruder results in imparting energy to the material, which is converted to heat in the conveyed material. When the heat transfer from the extruder energy consumed in transporting the material is not sufficient by itself to obtain the temperature necessary to produce the desired dispersion or solution of a FORMULA I compound in the polymeric matrix, generally, the extruder barrel is supplied with means for imparting additional heat to the material. Similarly, different sections of the extruder barrel can be heated or cooled as needed to maintain a particular temperature within one section of the extruder barrel or to extract heat into a different section of the extruder barrel to cool the material. as this is passing through this. In general, the extruder temperature, power and extruder transport speed are adjusted to provide the minimum temperature excursion and residence time necessary to ensure that a homogeneous dispersion or solution is prepared, thereby minimizing the amount of API that and subjected to degradation during the process.

[0047] In general, the extrudate emerging from an extruder is in a plastic state and solidifies on emergence from the barrel due to pressure release and cooling. During this transition, typically, the extrudate has a profile shape, for example noodles, bars, cylinders, etc., and is “cut” into conveniently sized pieces. Once the extruded parts are obtained, these can be further mechanically processed to provide a convenient form for incorporation into a dosage form, for example by grinding, grinding or sieving. As the term is used herein, the material emerging from the extruder, and any form in which the material is subsequently produced through mechanical processes, for example milling, grinding, mixing, sieving or granulating, is called the "extrudate". Exemplary extruders include those supplied by Leistritz, for example a Leistritz 27 mm twin screw extruder, and those supplied by Thermo-Fisher, for example a Thermo-Fisher 16 mm twin screw extruder. This equipment is generally equipped with means of heating the extruder barrel allowing it to be used in a "hot melt extrusion" operation.

[0048] Once the extrudate is produced in a form convenient for further processing, it can be incorporated into a formulation for use in providing a dosage form suitable for oral administration, for example, a formulation adapted for pressing into tablets or fill into capsules. To obtain the dissolution and disintegration targets necessary to effectively administer a compound of FORMULA I in providing migraine therapy, a formulation is prepared which comprises the finished extrudate, preferably milled to provide a powder form which is easily mixed with the others. formulation constituents, a disintegration system and other excipients, for example, diluents and lubricants, useful in preparing a formulation suitable for tabletting. For use in a formulation of the present invention, the disintegrant system comprises a conventional disintegrant, for example, croscarmellose sodium or crospovidone, and powdered sodium chloride, where "powdered sodium chloride" has the meaning given herein.

[0049] For use in a disintegration system of the present invention, the phrase "powdered sodium chloride" means sodium chloride that has been processed to a form having a particle distribution that produces the following values: (i) d50 of less than about 210 microns, for example about 195 microns; (ii) d10 of less than about 50 microns, for example, between 43 microns and 44 microns; (iii) a d90 of less than about 470 microns, eg about 460 microns, and wherein the material has a volume average diameter of less than about 240 microns, eg about 230 microns. An example of such a type of sodium chloride that is commercially available is provided by Avantor® under the product label “Sodium Chloride, Powder, USP GenAR® product no. 7540”.

[0050] The data presented in Table II illustrate the need to use powdered sodium chloride in the disintegration system in the formulations of the invention. Therefore, test tablets comprising an extrudate of the invention (said extrudate comprising a PVP-VA matrix, a compound of FORMULA IA (FIA-H), and TPGS), a diluent comprising microcrystalline cellulose and a disintegration system consisting of croscarmellose sodium and the salt shown in the left column of Table II were subjected to a disintegration test in accordance with USP 31-NF26 Chapter 701 in a standard disintegration test device (Pharamatron DT50) using aqueous HCl (pH 1, 8) as a disintegration medium at 37°C. As reflected in Table II, surprisingly, only the tablet using sodium chloride powder in the disintegration system was able to satisfy the disintegration target of less than 5 minutes (controlled tablet compression force to provide tablets of hardness and thickness consistent for all formulations). TABLE II

[0051] Furthermore, when equivalent tablets were manufactured using powdered sodium chloride alone, without croscarmellose sodium, it was found that tablet disintegration times also exceeded 5 minutes. Therefore, in some embodiments, it is preferable that the disintegrant system comprises a conventional disintegrant in conjunction with powdered sodium chloride, and more preferably in a 1:1 weight ratio, powdered sodium chloride:disintegrant. Without being bound by theory, it is believed that powdered sodium chloride exhibits dissolution kinetics that are rapid compared to the rate of gel formation of the polymeric matrix when a tablet of the invention is exposed to the intended dissolution environment (human GI tract ). Again, without being bound by theory, sodium chloride powder is believed, by virtue of its particulate profile, to have a combination of desirable dissolution kinetics and the ability to form quickly enough (faster than the rate of formation of matrix polymer gel) a local boundary layer of sufficient ionic strength to inhibit gel formation in the matrix polymer, and thereby to facilitate the release of a compound of Formula I from the compressed formulation, which would otherwise be inhibited by formation gelled into the matrix polymer. It will be appreciated that other salts, if provided in a form that performs the same combination of rapid dissolution kinetics and the ability to rapidly form a local boundary layer of sufficient ionic strength to inhibit gel formation, can also be used in a formulation of the invention. without breaking with the scope of the invention defined herein.

[0052] In the formulations of the invention, a suitable disintegrant for use in the disintegration systems of the invention is, for example, croscarmellose sodium (crosslinked sodium carboxymethylcellulose polymer), for example, the AC-Di-Sol® line of polymers available from FMC. It will be appreciated that other disintegrants can be used to provide an effective disintegration system, for example crospovidone, if these are used in accordance with the other aspects of the disintegration system described herein and do not depart from the scope of the invention.

[0053] The compounds of Formula I are intended for the treatment of migraine, and as such, a rapid release formulation is thought to be important in providing a therapeutic benefit to human patients to whom such a tablet is administered.

[0054] As is known, two qualities of tablet and capsule dosage forms important for releasing an active pharmaceutical compound from them can be demonstrated using standard tests to measure the disintegration time and/or the dissolution time of the dosage form dosage. A disintegration test measures the amount of time required for the dosage form to visibly disintegrate and wash out of a standard basket contained in a standard device under standard operating conditions. A standard disintegration test is described for tablets and capsules in USP 31-NF26, Chapter 701, starting on p 266. There are equivalents to these, described, for example, in the European Pharmacopoeia and the Japanese Pharmacopoeia, whose standard tests are generally accepted. in the regulatory bodies of most countries. As the term is used herein with reference to the formulations and tablets of the invention, "disintegration time" means: as determined according to a test in accordance with this standard operation at 37°C using aqueous HCl (pH 1.8) as a disintegration fluid.

[0055] Dosage forms intended for oral administration can also be measured in a dissolution test, in which the time rate release of an amount of therapeutic compound dissolved in a standard medium in a standard device is measured after introducing the dosage form in the test medium. A standard dissolution test for tablets and capsules is described, for example, in USP 36, Chapter 711. Equivalent tests are described in the European Pharmacopoeia and Japanese Pharmacopoeia, and with guidance from the US FDA, for example, in “Guidance for Industry , Dissolution Test of Immediate Release Solid Oral Dosage Forms” published August 1997 by the U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, pp 1-13 and the references cited therein. As the term is used herein with reference to the formulations and tablets of the invention, "disintegration time" means: as determined according to a test in accordance with this standard in a standard dissolution device equipped with USP 2 paddles, operated at 50 rpm , in 900 ml of simulated gastric fluid (pH 1.8) at 37°C.]

[0056] In one aspect, the invention provides a formulation adapted to prepare tablets comprising an extrudate of the invention, a disintegration system comprising sodium chloride powder and croscarmellose sodium, and other excipients, for example diluents, glidants and lubricants , in amounts where, once the formulation is compressed into a tablet having a hardness of about 12 kP to about 16 kP, and in some embodiments, from 12 kP to about 18 kP, it provides a release of tablet of greater than 90% of the API contained therein in less than about 20 minutes when subjected to dissolution testing in a standard dissolution device equipped with USP 2 paddles operated at 50 rpm in 900 ml of simulated gastric fluid ( pH 1.8) at 37°C, according to the procedures described in “Guidance for Industry, Dissolution Test of Immediate Release Solid Oral Dosage Forms” published in August 1997 by the U.S. Department of Health and Human Services, Food and Drug Administration , Center for Drug Evaluation and Research, pp 1-13 and references therein, where tablet hardness exceeds.

[0057] Where tablet hardness is used herein, this is indicated for a tablet having a target weight of 500 mg and a capsule form or a target weight of 652.2 mg in a capsule form. Therefore, as the term is used herein, tablets having a hardness in the range of 12 kPa to 16 kPa have a corresponding tensile strength of about 1.75 MPa, and tablets having a hardness in the range of 19 kPa to 22 kPa have a tensile strength of about 2.75 Mpa.

[0058] The formulations of the invention used in preparing oral dosage forms (i.e., tablets or capsules) may also comprise other excipients. For example, a typical formulation of the invention directed to the preparation of a compressed tablet may contain a diluent (for example, mannitol, article of commerce, and/or microcrystalline cellulose, for example Avicel®); a glidant (e.g., colloidal silica, e.g. Cab-O-Sil®); and a lubricant (eg sodium stearyl fumarate, article of commerce). It will be appreciated that in the formulation compositions of the invention, other diluents, glidants, and lubricants can be substituted to effect similar formulations.

[0059] The following definitions apply to excipients that may be used in the formulations of the invention as the terms are used herein: a diluent is an excipient that increases the mass of a dosage form, typically where the active pharmaceutical ingredient in the formulation is very potent to allow convenient processing or administration of a dosage form that does not include a diluent, or where the formulation itself, without a diluent, makes formation of the dosage form difficult (e.g., where an aliquot of the formulation without a diluent would be too little of a volume to aliquot into a tablet); a disintegrant is an excipient that expands and/or dissolves when placed in an aqueous environment, for example the gastrointestinal tract, which assists a tablet in breaking it and promotes the release of an active pharmaceutical ingredient contained in a tablet; A "disintegration system" is a combination of a conventional disintegrant and a rapidly dissolving salt that provides beneficial anti-gelling effects when placed in an environment in which the dosage form into which the disintegration system is incorporated is placed in an environment wherein the dosage form disintegrates, for example, simulated gastric fluid, a patient's gastrointestinal tract, or aqueous HCl at pH 1.8; a glidant is an excipient, eg colloidal silica, that increases the flow of a granular mixture by reducing interparticle friction.

[0060] Pharmaceutical formulations intended for the preparation of oral dosage forms (tablets and capsules) may also contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically palatable and palatable preparations.

[0061] The preparation of formulations of the invention suitable for use in providing solid oral dosage forms comprising a composition of the invention may involve mixing, roller compaction or wet granulation to densify and/or reduce the risk of segregation of the components during processing. subsequent handling (eg compression into tablets). Granulation steps can also be used to minimize the impact of raw material property variability (eg, excipient particle size) on subsequent processing (eg, tablet compression) and final product performance. Lubrication is typically carried out prior to roller compaction and tablet compression to reduce the material's tendency to stick to gripping surfaces (eg tablet tooling). In general, lubricants are stearic acid derivatives, for example magnesium stearate or sodium stearyl fumarate. Techniques and methods useful in preparing the dosage forms are known, for example, as described in Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition, 1999.

[0062] In general, the preparation of oral dosage forms of the pharmaceutical formulations of the invention requires that the pharmaceutical formulation of the invention (mixture of excipients, disintegrant system and composition of the invention) be compressed into a tablet or filled into a capsule. Tablets can be prepared in a variety of possible shapes (ellipsoidal, capsule, biconvex round, etc.). The powder can also be encapsulated in capsule strength (eg using hard gelatine capsules). Suitable techniques for preparing the solid oral dosage forms of the present invention are described in Remington's Pharmaceutical Sciences, 18th edition, edited by A. R. Gennaro, 1990, Chapter 89 and in Remington - The Science and Practice of Pharmacy, 21st edition, 2005, Chapter 45. In some embodiments of the present invention, it is preferred to prepare a tablet having a hardness of 16 kP or less, where the tablet is intended to provide the equivalent of 50 mg of a compound of FORMULA IA (100% free base ), placing 462.5 to 537.5 mg of the formulation into a tableting tool having Elizabeth Carbide Die Company® design number P-14305-B and pressing into a Korsch® tabletting press.

[0063] With reference to Figure 3, in general, the compositions of the invention are prepared by dry mixing various excipients with a ground dispersion (soluble polymeric matrix comprising API dispersed therein), and compressing the mixture into tablets.

[0064] The following is a description of the general procedures used in preparing the extrudate, preparing a liquid tabletting formulation comprising the extrudate, and preparing the tablets of the invention therefrom. The following examples only serve to illustrate the invention and its practice. The examples are not to be considered as limitations on the scope or spirit of the invention. Example I - Preparation of an extrudate comprising Kollidon® 64, TPGS and (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2- trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospirocyclopenta[b]pyridine-6,3'-pyrro[2,3-b]pyridine1-3- carboxamide (FIA-H), a liquid tabletting formulation and tablets prepared from this:

[0065] With reference to Figure 2, the extrudate comprising a water-soluble polymeric matrix dispersed therein, the API was prepared by: (i) forming a FIA-H/matrix polymer premix by mixing the dried from an amount of crystalline FIA-H and polyvinylpyrrolidone/vinyl acetate copolymer (matrix polymer) to provide a premix having an API:matrix polymer weight ratio of 1:3.75; (ii) feeding an amount of the API/matrix premix and an amount of alpha-tocopherol/fused propylene glycol succinate (TPGS) to provide a 19:1 weight ratio, API:TPGS premix into the extruder; and (iii) maintaining the extruder device at a gun temperature, feed rate and screw speed which provides an extrudate comprising a solid solution of the API in a matrix (polyvinylpyrrolidone-vinyl acetate/TPGS copolymer) comprising about 20% in weight of the active API.

[0066] Therefore, 1.318 kg of the FIA-H trihydrate (compound of Formula Ia in which all "Rb" are -H) was mixed with 4.382 kg of the matrix polymer. TPGS (0.300 Kg) was melted and added to the mixture of FIA-H and VA-64 in a high shear granulator. The blended API, VA-64 and TPGS were prepared in eight separate blending operations using a Diosna high shear granulator with a 6 L vessel, an impeller speed of 1000 rpm, a chopper speed of (600) rpm. In each operation, the mixer was operated for 1 minute to mix FIA-H and the matrix polymer, then molten TPGS was added via a pipette for 5 minutes of time maintaining impeller and chopper speed. After addition of TPGS, the mixture was blended for an additional 1 minute, maintaining impeller and chopper speed.

[0067] The blended material was fed into a 16 mm Thermo-Fischer extruder while maintaining a product temperature of about 146°C to about 160°C, die pressure of about 1.4 mPa to about of 1.6 mPa (about 14 bar to about 16 bar), a powder feed rate of 30 to 52 g/min, to provide 6.0 kg of an extrudate of the invention. This material was ground in a Fitz mill equipped with screen size 0 (0.027” (0.068 cm)) and using the following operating conditions: an impeller speed of 2000 to 4500 rpm, and impact: advanced blade direction. The ground extruded material was measured by passing it through a 600 micron screen, providing a powder (intermediate extrudate) having a VMD of approximately 195 microns when measured by QICPIC for use in preparing a blend for pressing into tablets (blend of tablet formation).

[0068] A tabletting mixture (6 kg) was prepared using 3.6 kg of extruded intermediate comprising the equivalent of 200 mg/g of 100% FIA-H free base, 1.160 kg of mannitol SD 10, 0.600 kg of sodium chloride powder, 0.600 kg of croscarmellose sodium, 0.01500 kg of colloidal silica, 0.09000 kg of sodium stearyl fumarate, and 0.5798 kg of Avicel PH102. Mixing speed was 25 rpm and mixing time was 5 minutes.

[0069] The tablet-forming mixture was subdivided into 1,250 kg subparts, and tablets corresponding to the hardness ranges of 12 to 16 kP, 19 to 22 kP, and 24 to 28 kP were prepared by compressing aliquots of each portion of the mixture of tablet forming on a Korsch X1100 equipped with top and bottom tools with the face design P14305-B, which is a flat oval tool measuring 14.68mm x 8.33mm.

[0070] Tablets having a hardness in the range of 12 kP to 16 kP were tested according to a test in accordance with USP 30 NF25 Chapter 711, device equipped with paddle stirrer with USP 2 paddles, operated at 50 rpm, in 900 ml of simulated gastric fluid (pH 1.8) at 37°C, these tablets meet the target release of 90% FIA-F contained in the dissolved tablet in less than 20 minutes. Example II - Preparation of an extrudate comprising Kollidon® 64, TPGS and (S)-N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5 -(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydro-spiro[cyclopenta[b]pyridine-6,3'-pyrrole [2,3-b]pyridine]-3-carboxamide) (FIA-F)), a liquid tabletting formulation and tablets prepared therefrom:

[0071] Using the general preparation shown in Example I, 1.421 kg of FIA-F (compound of FORMULA IA in which all “Rb” are -F) was mixed with 4.320 kg of matrix polymer in a 25, 0 l, drive speed set to 'fast', cutter speed set to 'high'. In the granulator 0.300 kg of TPGS was added during five minutes while maintaining the speed of the impellers and cutters. This blended material was hot melt extruded in a 16 mm Thermo-Fisher extruder set to provide a product temperature of 158°C, powder feed rate of 20 g/minute, and maintained die pressure of 0.2 at 0.4 mPa (2 to 4 bar), producing 4.52 kg of extrudate.

[0072] The extrudate prepared in this way (3.3 kg) was milled with a Fitz mill, sieve size 000 (0.20” (0.51 cm)), with a set of impact blades in the 'forward' direction and an impeller speed set to a target of 3000 rpm (2000 rpm to 6000 rpm). The milled extrudate was screened through a 600 micron screen producing 3.01 kg of a screened extrudate. A portion of the sieved material (3.0 kg) was mixed with sodium stearyl fumarate (0.05625 kg), silicon dioxide (0.01875 kg), microcrystalline cellulose (0.9750 kg), powdered sodium chloride ( 0.750 Kg) and mannitol (1.950 Kg) using a V-blender operating at 24 rpm.

[0073] Two aliquots of the tabletting mixture prepared above (1.957 kg) were pressed into tablets corresponding to the hardness ranges of 12 kP to 18 kP and 20 kP to 26 kP respectively, on a Korsch X1100 tableting press equipped with top and bottom tooling with oval face drawing tool measurement P10165-B (flat/flat) 15.88 mm x 8.81 mm with a target tablet weight of 652.2 mg.

[0074] The tablets were dissolved in a paddle stirring dissolution device using simulated gastric fluid at 37°C, paddle speed 50 rpm in a test in accordance with USP 30 NF25 Chapter 711, these tablets meet the target of release profile of 90% FIA-F contained in the tablet dissolved in less than 20 minutes, and the target of complete disintegration in less than 5 minutes when tested using a disintegration test in accordance with USP 31-NF26 Chapter 701 in a standard disintegration tester (Pharamatron DT50) using aqueous HCl (pH 1.8) as a disintegration medium at 37°C tested in aqueous HCl (pH 1.8) at 37°C.

[0075] While the foregoing specification teaches the principles of the present invention, with examples provided for purposes of illustration, practice of the invention encompasses all general variations, adaptations, and/or modifications that are within the scope of the following claims.

Claims (19)

1. Tablet, characterized in that it comprises: (a) an extrudate comprising: (i) a polymeric matrix which is a water-soluble polyvinylpyrrolidone/vinyl acetate copolymer; (ii) d-alpha-tocopheryl polyethylene glycol (TPGS); and (iii) a compound of Formula I, or a pharmaceutically acceptable salt thereof: Formula I, wherein "Ra" is independently -H or -F, and wherein the dispersing agent and compound of Formula I are dispersed within said polymeric matrix; and (b) a disintegration system comprising sodium chloride powder and croscarmellose sodium. 2. Tablet according to claim 1, characterized in that the length has a hardness of 12 kP to 18 kP, and in which the tablet achieves complete disintegration in less than 5 minutes in a standard disintegration test in accordance with USP 31-NF26 Chapter 701 using aqueous HCl (pH 1.8) at 37°C 3. Tablet according to claim 1, characterized in that the disintegration system comprises a 1:1 weight ratio of powdered sodium chloride and sodium croscarmellose. 4. Tablet according to claim 1, characterized in that the tablet has a hardness of 12 kP to 18 kP, and in which when said tablet is subjected to a dissolution test in accordance with USP 30 NF25 Chapter 711 , in a paddle stirring device equipped with USP 2 paddles, operated at 50 rpm, in 900 ml of simulated gastric fluid (pH 1.8) at 37°C releases at least 90% of the compound of Formula I contained therein in less than 20 minutes. 5. Tablet according to claim 1, characterized in that the tablet has a tensile strength of 1.75 MPa, and in which when said tablet is subjected to a dissolution test in accordance with USP 30 NF25 Chapter 711, in a paddle stirring device equipped with USP 2 paddles, operated at 50 rpm, in 900 ml of simulated gastric fluid (pH 1.8) at 37°C releases at least 90% of the compound of Formula I contained therein in less than 20 minutes. 6. Tablet according to any one of claims 1 to 5, characterized in that the dispersing agent in said extrudate is d-alpha-tocopheryl polyethylene glycol succinate (TPGS). 7. Tablet according to any one of claims 1 to 6 characterized in that the compound of Formula I is a compound of Formula Ia, or a salt thereof Formula Ia, where each of "Rb" is -H or each of "Rb" is -F. 8. Tablet according to any one of claims 1 to 6 characterized in that it also comprises: (a) mannitol; (b) colloidal silica; (c) microcrystalline cellulose; and (d) sodium stearyl fumarate. 9. Tablet according to claim 6 or 7, characterized in that the compound of Formula I or Formula Ia is (S)-N-((3S,5S,6R)-6-methyl-2-oxo-1 - (2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[ b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide. 10. Tablet according to claims 6 or 7, characterized in that the compound of Formula I or Formula Ia is (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5 - phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6, 3'-pyrrolo[2,3-b]pyridine]-3-carboxamide. 11. Tablet according to any one of claims 1 to 10, characterized in that said extrudate comprises 50% by weight of said tablet and said extrudate comprises 5% by weight to 23% by weight of a compound of Formula I or Formula Ia. 12. Tablet according to any one of claims 1 to 10, characterized in that said powdered sodium chloride has: (i) a d50 value of less than 210 microns; (ii) a d10 value of less than 50 microns; and (iii) a d90 value of less than 470 microns. 13. Tablet according to any one of claims 1 to 9, characterized in that the water-soluble polymeric matrix of said extrudate is a copolymer having a 6:4 ratio of polyvinylpyrrolidone/vinyl acetate monomeric unit. 14. Formulation suitable for pressing into a tablet, said formulation characterized in that it comprises: a) an extruded composition comprising a polyvinylpyrrolidone/vinyl acetate copolymer matrix (PVP-VA copolymer) soluble in water and dispersed in it: (i) an active compound of Formula Ia, or a pharmaceutically acceptable salt thereof: Formula Ia, wherein all Rb are -H or all Rb are -F; and (ii) polyethylene glycol tocopheryl succinate (TPGS), wherein said compound of Formula Ia comprises from 5% by weight to 23% by weight of said extrudate and the TPGS comprises at least 5% by weight of said extrudate; and b) a disintegration system comprising: (i) croscarmellose sodium; and (ii) powdered sodium chloride, said disintegration system comprising 20% by weight of said formulation. 15. Formulation according to claim 14, characterized in that it comprises: (a) mannitol; (b) colloidal silica; (c) microcrystalline cellulose; and (d) sodium stearyl fumarate, and wherein said powdered sodium chloride is characterized by: (i) a d50 value of less than 210 microns; (ii) a d10 value of less than 50 microns; and (iii) a d90 value of less than 470 microns. 16. Formulation according to claims 14 or 15 characterized by the fact that the ratio by weight of the compound of Formula Ia: powdered sodium chloride: sodium croscarmellose is 9:10:10. 17. Formulation according to any one of claims 14 to 16, characterized in that said compound of Formula Ia is (S)-N-((3S,5S,6R)-6-methyl-2-oxo- 1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta [b]-pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide or (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5 -phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3' -pyrrolo[2,3-b]pyridine]-3-carboxamide. 18. Formulation according to any one of claims 14 to 17, characterized in that said extrudate is present in an amount that provides 50% by weight of the formulation. 19. Tablet, characterized in that it is manufactured by pressing a formulation as defined in any one of claims 14 to 18 in a tablet press to provide a tablet with a tensile strength of 1.75 MPa.