Pharmaceutical composition comprising olaparib

Abstract

The invention relates to a pharmaceutical formulation comprising olaparib as active agent in solid dispersion with a matrix polymer. In particular, the present invention relates to a pharmaceutical formulation comprising olaparib in a solid dispersion with a matrix polymer that comprises polyvinylpyrrolidone, a daily pharmaceutical dose of olaparib provided by such a formulation and the use of polyvinylpyrrolidone in a solid dispersion composition with Olaparib for increasing the bioavailability and / or stability of Olaparib, and for treating cancer in a patient.

Description

[0001] Pharmaceutical composition comprising Olaparib

[0002] The invention relates to a pharmaceutical formulation comprising olaparib as active agent in solid dispersion with a matrix polymer.

[0003] In particular, the present invention relates to a pharmaceutical formulation comprising olaparib in a solid dispersion with a matrix polymer that comprises polyvinylpyrrolidone.

[0004] The invention also relates to a daily pharmaceutical dose of olaparib provided by such a formulation.

[0005] In addition, the invention relates to the use of polyvinylpyrrolidone in a solid dispersion composition with Olaparib for increasing the bioavailability and / or stability of Olaparib, and for treating cancer in a patient.

[0006] Olaparib is the INN of 4-[3-(4-cyclopropanecarbonyl-piperazine-l- carbonyl)-4-fluoro-benzyl] -2H-phthalazin-1-one and has the following structure:

[0007] It is marketed under the name Lynparza® and provided in the form of film tablets comprising a dosage strength of 100 mg or 150 mg Olaparib . Olaparib is disclosed and exemplified in International Patent Application Publication No. WO 2004 / 080976 Al (compound 168). It is a poly (ADP-ribose)polymerase (PARP) inhibitor, which is used for the treatment of adults with suspected deleterious germline or somatic BRCA gene mutated ovarian, breast, or pancreatic cancer, or for suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutated prostate cancer.

[0008] Oral delivery is the preferred way of drug administration since oral formulations are cheap to produce and convenient for the patient. However, oral formulations of crystalline drug substances with poor aqueous solubility often exhibit poor solubility and low dissolution rates, resulting in low bioavailability and poor therapeutic performance.

[0009] Olaparib is classified by the Biopharmaceutical Classification System (BCS) as being a class 4 drug meaning it has both low solubility and low permeability. To enable sufficient efficacy, it is therefore critical to find forms of olaparib with the highest possible solubility and bioavailability.

[0010] Olaparib exists in multiple polymorphic forms, as well as solvated and hydrated forms, which have been disclosed, for example, in WO 2008 / 047082 A2 (Form A), WO 2009 / 050469 Al (Form L), WO 2010 / 041051 Al (amorphous)and WO 2017 / 123156 Al (Forms I and II). The original marketed formulation contained Form A which has pH independent aqueous solubility of about 0.1 mg / ml. As the polymorphic crystalline forms of olaparib have such low solubility, a solubility enhancing formulation was required to achieve sufficient bioavailability. The original marketed formulation was a capsule, where olaparib Form A was micronized and formulated as a crystalline dispersion in the semi-solid Lauroyl macrogolglyceride (LMG) matrix. This formulation improved the bioavailability of pure crystalline olaparib. However, due to the amount of LMG needed in the formulation only 50 mg capsules were possible resulting in patients requiring 16 capsules per day.

[0011] By converting the crystalline form of a drug into its amorphous counterpart, the solubility and dissolution rate of the drug substance is increased, leading to improved bioavailability and therapeutic efficacy.

[0012] For example, in WO 2022 / 258625 Al is disclosed a co-amorphous form of beta-lactoglobulin and. olaparib, wherein the concentration of the drug substance in the co-amorphous form is from 10% to 90% w / w based on the total weight of the co-amorphous form.

[0013] However, amorphous drug forms are physically unstable and tend to re-crystallize back into the poorly soluble crystalline form during storage.

[0014] To provide Olaparib in a form that allows long-term storage but with good dissolution properties WO 2023 / 084311 Al suggests use of Olaparib : hydroxybenzoic acid cocrystals as an active pharmaceutical ingredient. Preferred 1:1 olaparib : hydroxybenzoic acid cocrystals are selected from the group consisting of a 1:1 olaparib gentisic acid cocrystal, 1:1 olaparib 2 ,4-dihydroxybenzoic acid cocrystal, 1:1 olaparib salicylic acid cocrystal, and a 1:1 olaparib 3,4- dihydroxybenzoic acid cocrystal.

[0015] According to another method, the active pharmaceutical ingredient is directly delivered to the tumour tissue. A microsphere suspension is introduced into a blood vessel supplying the tumour, where it lodges, causing an embolus that shuts down blood supply to local tissue. This approach is known as transarterial embolization or TAE. In one approach, a drug may be incorporated into the embolic material and is released into the tissues surrounding the embolus. This approach is known as transarterial chemoembolization or TACE. Embolic microspheres have been prepared from a variety of biocompatible materials, including both natural and synthetic polymers.

[0016] In WO 2023 / 122292 Al is described a polymer microsphere comprising a polymer and an inhibitor of the enzyme poly ADP ribose polymerase (PARP inhibitor) wherein the PARP inhibitor is held within the polymer microsphere and is elutable from the microsphere in aqueous media. A preferred PARP inhibitor is Olaparib .

[0017] To reduce the high pill load necessary for oral application of olaparib, a tablet formulation was developed that contains an amorphous solid dispersion of olaparib in a matrix with copovidone polymer, formed using a melt extrusion method. This tablet formulation showed faster dissolution compared to the capsule formulation and subsequently higher bioavailability, resulting in the daily dose of olaparib being lowered from 800 mg to 600 mg. Use of an amorphous form of olaparib also overcame the issue of polymorph conversion, although this approach brings a number of disadvantages:

[0018] 1) amorphous forms, being metastable, are generally less stable than crystalline forms in terms of storage, therefore requiring large amounts of stabiliser to maintain the amorphous form;

[0019] 2) amorphous forms always carry the risk of re-crystallisation on storage; and

[0020] 3) as the polymer (copovidone) used in the tablet matrix is hygroscopic , the tablet formulation requires protective packaging to prevent moisture uptake.

[0021] Further attempts have been made by using povidone as a matrix material . In CN 104434809 B is described an olaparib solid dispersion preparation and a preparation method thereof. For preparation of tablets, olaparib and povidone are dissolved in an organic solvent and subsequently a solid dispersion is prepared by solvent evaporation or spray drying. A lubricant, a disintegrant and a diluent is added to the obtained powder and after mixing and tableting tablets are obtained. According to a further method the solid dispersion is prepared by mixing olaparib, povidone and part of the lubricant through melt extrusion. Then a disintegrant, a diluent and the remaining lubricant are added and mixed and tableted to obtain the tablet. Povidone K25, povidone K30 or povidone K90 is used as a matrix material.

[0022] In CN 106137998 A is described a pharmaceutical composition of olaparib, comprising olaparib or a salt thereof and a carrier. The carrier preferably comprises one or more of povidone 12PF, povidone 17PF or povidone K25. Povidone 12PF is particularly preferred. The olaparib or its salt and the carrier are contained in the pharmaceutical composition preferably in the form of a solid dispersion. The solid dispersion is preferably prepared by hot melt extrusion or spray drying.

[0023] Thus, methods for stabilizing amorphous drug forms are warranted by the pharmaceutical industry. Notably, there is a need in the art for new excipients that can further improve the stability and / or solubility properties of olaparib formulations.

[0024] It would be further desirable to identify a suitable matrix polymer that could be formulated into a solid dispersion with the drug using any of the available solid dispersion techniques without the need for additional surfactants / plasticisers as it would be appreciated that the presence of certain extraneous excipients could compromise the stability of olaparib (e.g. the ability to remain in amorphous form).

[0025] The present invention aims to provide a formulation of olaparib

[0026] (4- [3"(4-cyclopropanecarbonyl-piperazine-l-carbonyl)-4-fluoro- benzyl] -2H-phthalazin-l-one) that minimises the size and / or number of tablets or capsules required for the therapeutically effective dose, ideally to fewer than 4 units, preferably only one or two units .

[0027] The inventors have now surprisingly found that the therapeutic potential of olaparib can be increased by formulating olaparib in a solid dispersion in a matrix polymer comprising Polyvinylpyrrolidone (PVP). The matrix polymer Polyvinylpyrrolidone (PVP), also commonly called polyvidone or povidone, was found to be particularly suitable as it could be used in hot melt extrusion without the need of a plasticiser and it provides a product with acceptable stability, even at 30% drug loading in the final product (e.g. tablet).

[0028] Use of the matrix polymer caused little degradation of the active agent neither during production of the formulation nor during storage of the pharmaceutical formulation. The pharmaceutical formulation has good dissolution properties such that the active substance dissolves rapidly in an aqueous medium such as intestinal fluid. A good bioavailability of the active compound olaparib therefore is achieved.

[0029] The active compound olaparib may be present in a crystal form, e.g. in the form of olaparib hydrate (for example, monohydrate) or anhydrous olaparib, or may be present in an amorphous form thereof, or a mixture thereof.

[0030] In an embodiment wherein olaparib is present as an amorphous solid, the solubility and elution rate increase and thereby bioavailability can be improved. Furthermore, the physical stability of the solid dispersion is improved by using polyvinylpyrrolidone as a matrix material.1

[0031] According to an embodiment, olaparib is present in the pharmaceutical formulation in amorphous form. If the olaparib is amorphous, since the solubility increases as compared with crystal form, there is advantage of further increased in vivo absorption ratio.

[0032] The term "solid dispersion" as used herein means systems in which an active agent is dispersed in an excipient carrier forming a matrix. With respect to the state of the drug in the systems, solid dispersions in this sense can include compositions in which the drug is dispersed as discrete domains of crystalline or amorphous drug, or as individual molecules within an excipient carrier. The term "solid dispersion" used in the present invention refers to a form wherein the material to be dispersed (olaparib) in crystal or amorphous form is dispersed in a continuous phase formed by a matrix polymer comprising polyvinylpyrrolidone.

[0033] More preferably, term "solid dispersion" refers to a form wherein the drug in amorphous form is dispersed in an amorphous polymer. In the present invention the definition of a solid dispersion does not encompass physical mixtures from dry or wet mixing or dry blending operations.

[0034] The solid dispersion generally comprises drug and polymer, and in some cases, it may further comprise other additive (s) such as surfactant, plasticizer, disintegrating agent, etc.

[0035] In an embodiment, the solid dispersion does not comprise a surfactant .

[0036] According to an embodiment the active agent Olaparib is in stable amorphous form.

[0037] By the term "in stable amorphous form" is meant that the stability (ability to remain in amorphous form and resist converting to crystalline form) of the amorphous state is extended in the solid dispersion formulation of the invention relative to the stability of the amorphous state of olaparib on its own. In the formulations of the invention, at least some of the olaparib may be present in amorphous form in the solid dispersion with the matrix polymer.

[0038] Whether or not drug is present in amorphous form can be determined by conventional thermal analysis, or X-ray diffraction. In one embodiment, at least 25% of the olaparib in the formulation is present in amorphous form, as measured using XRPD. More preferably, this amount is at least 30%, 40%, 50%, 75%, 90%, 95%, as measured using XRPD. The most preferred embodiment is where 100% of the Olaparib in the formulation is in amorphous form. Current XRPD tools and techniques may only be able to detect >5% crystalline form, and thus the inability to detect crystalline form may mean that the sample is between 95% and 100% amorphous.

[0039] According to a preferred embodiment at least 90% of the active agent olaparib is in amorphous form.

[0040] According to a further embodiment, at least 95% of the active agent olaparib is in amorphous form.

[0041] According to an embodiment, the solid dispersion is stable for at least 3 months. A stable dispersion is understood to be a dispersion wherein after storage for at least 3 months, preferably 6 months, further preferred at least 12 months, further preferred at least 18 months, and further preferred at least 24 months at most 5% of the amorphous olaparib has been crystallized.

[0042] Crystallization can be detected by e.g. XRD-spectroscopy.

[0043] The active agent is embedded in a matrix polymer, wherein the matrix polymer is at least partially formed of polyvinylpyrrolidone .

[0044] According to an embodiment, the matrix polymer is essentially formed of polyvinylpyrrolidone. Polyvinylpyrrolidone (PVP), also commonly called polyvidone or povidone, is a water-soluble polymer compound made from the monomer N-vinylpyrrolidone . PVP is available in a range of molecular weights and related viscosities.

[0045] According to an embodiment, the polyvinylpyrrolidone is present as a homopolymer, i.e. is formed only of repeating units formed from N-vinylpyrrolidone. The polyvinylpyrrolidone is, according to an embodiment, in the form of a linear polymer, i.e. has essentially no branches and / or cross-linking present in the polymer.

[0046] According to an embodiment the matrix polymer does not comprise copovidone. Copovidone is understood to be cross-linked polyvinypyrrolidon .

[0047] According to an embodiment the polyvinylpyrrolidone has a K-value of less than 27.

[0048] Polyvinylpyrrolidone products can be characterized by their K- value. The K-value is a classification commonly used in the plastics industry and is directly related to the average molar mass of the polymer. This means that the degree of polymerization and therefore the chain length can be indirectly deduced from the K-value.

[0049] Exemplary K-values are shown in the following table: The K-value introduced by Fikentscher is determined viscometrically and is a measure of the molecular weight of a polymer [W. Kern und Schulz, in Houben Weyl, 14 / 1, S. 83ff., Georg Thieme Verlag, Stuttgart, 1961]. The K-value is calculated using the following formula: -togiiei^c where rjrei is the relative viscosity, the quotient of the viscosity of the polymer solution and the solvent, and c is the concentration of the polymer solution.

[0050] The K-value is calculated from the relative viscosity of polyvinylpyrrolidones in water according to the Ph.Eur. and US monographs. It commonly forms also part of the commercial name of the polyvinylpyrrolidone.

[0051] According to a further embodiment, the polyvinylpyrrolidone has a K-Value within a range of 10 to 27.

[0052] According to a further embodiment, the polyvinylpyrrolidone has a K-value of less than 20.

[0053] According to an embodiment, the polyvinylpyrrolidone has a K-value of less than 17. According to an embodiment, the K-value is less than 16.

[0054] According to an embodiment, the K-value is at least 12. According to a further embodiment, the polyvinylpyrrolidone has a K-value of more than 12. According to an embodiment the K-value is larger than 13.

[0055] According to an embodiment, the polyvinylpyrrolidone has a K-value of 15, preferably is povidone K15. "K15" designates a grade of polyvinylpyrrolidone with a particular molecular weight and a particular K-value as designated in the above table.

[0056] According to a further embodiment, the matrix polymer has a glass transition temperature of less than 145°C.

[0057] According to a further embodiment, the matrix polymer has a glass transition temperature within a range of 120 to 140°C, according to a further embodiment within a range of 125 to 135°C.

[0058] Glass transition temperature can be determined by Differential Scanning Calorimetry (DSC).

[0059] According to the invention, the matrix polymer comprises polyvinylpyrrolidone. Preferably, the matrix polymer comprises polyvinylpyrrolidone in an amount of at least 50 wt.-%, according to a further embodiment in an amount of at least 70 wt-%, according to a still further embodiment in an amount of at least 90% and according to a still further embodiment in an amount of at least 95%.

[0060] According to a still further embodiment, the matrix polymer essentially consists of polyvinylpyrrolidone.

[0061] It has been found that advantageous properties of the pharmaceutical composition may be obtained with a polyvinylpyrrolidone that has an average molecular weight Mw within a range of 2.500 to 25.000 g / mol, according to a further embodiment within a range of 5.000 to 20.000 g / mol, according to a still further embodiment within a range of 6.000 to 15.000 g / mol.

[0062] When using polyvinylpyrrolidone of lower molecular weight, in particular with an average molecular weight Mw within a range of 2500 to 25.000 g / mol, more preferred within a range of 6000 to 15.000 g / mol, less decomposition of the active material olaparib is observed, in particular observed during melt extrusion. According to a further embodiment, the matrix polymer comprises polyvinylpyrrolidone and at least one further polymer. A suitable further polymer is e.g. polyethylene glycol (PEG).

[0063] According to the various aspects of the invention a particular ratio of olaparib : matrix polymer by weight is from 1:0.25 to 1 : 10. More preferably the lower limit of the range is 1 : 1.4, 1 : 1.6 or 1 : 2. Preferably, the upper limit of this range is 1 :5, 1:3, 1 : 2.4 or 1 : 2.2. Suitable ratios are 1 : 2,4, 1 : 3 and 1 :4.

[0064] A particular preferred range is 1 : 2.0 to 1 : 3.0.

[0065] By a higher amount of matrix polymer a quicker release of the active material olaparib and therefore a higher bioavailability can be achieved.

[0066] The solid dispersion formulations of the invention exhibit increased bioavailability and drug loading potential and are thus likely to require fewer dose units compared to conventional / immediate release olaparib formulations.

[0067] According to an embodiment, the amount of active agent comprised in the solid dispersion is at least 15 wt.%, according to a further embodiment is at least 20 wt.%.

[0068] According to a further embodiment, the amount of active agent comprised in the solid dispersion is selected within a range of 10% to 70%, preferably from 15 to 50% (more preferably 20 to 30% or 25 to 35%) by weight of the solid dispersion.

[0069] The solid dispersion is preferably made by solvent evaporation or melt extrusion. Melt extrusion is particularly preferred. In a solid dispersion obtained by melt extrusion a stable amorphous phase of olaparib can be obtained.

[0070] Preparing the solid dispersion by solvent evaporation typically comprises the steps of dissolving the olaparib and the polymer in a common solvent and evaporating the solvent. The solvent can be routinely selected according to the polymer used. Examples of solvents are acetone, acetone / dichloromethane, methanol / dichloromethane, acetone / water , acetone / methanol, acetone / ethanol , dichloromethane / ethanol or ethanol / water. Methods for evaporating solvent include rotary evaporation, spray drying, lyophilisation and thin film evaporation. Alternatively solvent removal may be accomplished by cryogenic freezing followed by lyophilisation.

[0071] Preparing the solid dispersion by melt extrusion typically comprises the steps of adding olaparib, or a pharmaceutically acceptable salt or solvate thereof, and the polymer comprising polyvinylpyrrolidone, and any additional optional excipients, including plasticisers, to a melt extrusion apparatus which then heats and mixes and finally extrudes the solid dispersion product. The extruder heats the mixture to a temperature high enough to melt the mixture but low enough so as to not degrade the constituents .

[0072] The extrudate of the solid dispersion product may then be milled and optionally sieved to obtain a powder suitable for formation of granules or pressing tablets.

[0073] According to an embodiment the extrudate powder has a D90of less than 350 / zm; according to a further embodiment has a D90of less than 320 / zm .

[0074] D90is understood to be a value, wherein less than 90% of the particles have a diameter of less than Dao.

[0075] The particle size and the particle size distribution can be determined by methods known to the skilled artisan. A suitable Method is e.g. laser diffraction.

[0076] According to an embodiment, the formulation is provided in the form of a unit dose, e.g. a tablet, a pill or a capsule. According to an embodiment, the unit dose comprises 10 to 1500 mg, according to a further embodiment comprises 25 to 600 mg olaparib.

[0077] In various embodiments, the dose comprises 1500, 1250, 1000, 800, 700, 600, 500, 450, 400, 300, 250, 225, 200, 175, 150, 125, 100, 75, 50, 25, 15 or 10 mg of olaparib. In particular embodiments, the dose comprises 25, 50, 100, 150, 200 or 400 mg of olaparib.

[0078] According to a particularly preferred embodiment, the unit dose comprises the active agent in an amount of 100 mg or 150 mg olaparib.

[0079] Additional excipients may be included in the formulation or dose. For example, the formulation or dose may comprise one or more fillers, binders, disintegrants and / or lubricants.

[0080] Suitable fillers include, for example, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g. microcrystalline cellulose, cellulose), calcium sulphate, xylitol and lactitol. Mannitol is a preferred filler.

[0081] Suitable binders include, for example, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copovidone, gelatine and sodium alginate.

[0082] A preferred binder is hydroxypropyl cellulose (HPC), and / or a hydroxypropylmethyl cellulose, in particular hydroxypropylmethyl cellulose (HPMC) that in 2 % by weight in water at 20 °C has a viscosity of 4.0 to 6.0 cP. This particular HPMC quality is marketed e.g. under the name Methocel™ E5.

[0083] According to an embodiment the amount of the binder in the formulation or dose is selected within a range of 0% to 12%, preferably from 0.4% to 6% by weight of the formulation. According to a particularly preferred embodiment, the formulation comprises as a binder hydroxypropyl cellulose (HPC) in an amount of 0% to 6% by weight of the formulation and hydroxypropylmethyl cellulose (HPMC) in an amount of 0% to 6% by weight of the formulation.

[0084] According to another particularly preferred embodiment, the formulation comprises as a binder an amount of hydroxypropyl cellulose (HPC) is between 0% and 6%, preferably between 0.2% and 3%, by weight of the formulation and the amount of hydroxypropylmethyl cellulose (HPMC) is between 0% and 6%, preferably between 0.2% and 3%, by weight of the formulation, wherein the amount of at least one of hydroxypropyl cellulose (HPC) or hydroxypropylmethyl cellulose (HPMC) is more than 0% by weight of the formulation.

[0085] Suitable disintegrants include, for example, croscarmellose sodium, crospovidone, sodium starch glycollate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Hydroxypropyl cellulose, in particular low-substituted hydroxypropyl cellulose (HPC-L), is preferred.

[0086] Suitable lubricants include, for example, magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil, hydrogenated castor oil, medium-chain triglycerides, poloxamer, polyethylene glycol and talc.

[0087] Additional conventional excipients, which may be added, include preservatives, stabilisers, antioxidants, silica flow conditioners, antiadherents or glidants.

[0088] Other suitable fillers, binders, disintegrants, lubricants and additional excipients which may be used are described in the Handbook of Pharmaceutical Excipients, 5th Edition (2006); The Theory and Practice of Industrial Pharmacy, 3rd Edition 1986; Pharmaceutical Dosage Forms 1998; Modern Pharmaceutics, 3rd Edition 1995; Remington's Pharmaceutical Sciences 20th Edition 2000 .

[0089] In certain embodiments, one or more fillers will be present in an amount of 1 to 70% by weight of the formulation or dose.

[0090] In certain embodiments, one or more binders will be present in an amount of 2 to 40% by weight of the formulation or dose.

[0091] In certain embodiments, one or more disintegrants will be present in an amount of 1 to 20%, and especially 4 to 10% by weight of the formulation or dose.

[0092] It will be appreciated that a particular excipient may act as both a binder and a filler, or as a binder, a filler and a disintegrant. Typically, the combined amount of filler, binder and disintegrant comprises, for example, 1 to 90% by weight of the formulation or dose .

[0093] In certain embodiments, one or more lubricants will be present in an amount of 0.5 to 3%, and especially 1 to 2% by weight of the formulation or dose.

[0094] In an embodiment, the solid dispersion may further comprise a surfactant .

[0095] The surfactant may be, for example, an anionic surfactant. The anionic surfactant may be sodium dodecyl sulfate, sodium lauryl sulfate, sodium N-lauroyl sarcosylate, salt of N-long chain acyl glutamate, sucrose fatty acid ester, poly oxyethylene hydrogenated castor oil, sorbitan fatty acid ester, copolymer of polyoxyethylene and polyoxypropylene, or a combination thereof, or it may be sodium dodecyl sulfate.

[0096] The surfactant may be used, for example, in an amount of 0.1 to 50%, preferably ^5% (eg, 1 to 2%) by weight of the solid dispersion. The presence of a surface-active agent provides a further enhancement of the increase in therapeutic potential achieved with the present invention.

[0097] In certain embodiments, one or more plasticisers will be present in the solid dispersion in an amount of 0.1% to 50%, preferably <5% (e.g. 1 to 2%) by weight of the solid dispersion. The presence of a plasticiser may enhance processability of the solid dispersion, for example when a melt extrusion process is used. Examples of suitable plasticisers include: acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, glycerine, glycerine monostearate, mannitol, mineral oil, lanolin alcohols, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine and triethyl citrate .

[0098] The invention also provides a daily pharmaceutical dose of olaparib wherein the dose comprises a therapeutically effective amount of olaparib in a solid dispersion with a matrix polymer wherein the matrix polymer comprises polyvinylpyrrolidone.

[0099] Embodiments of the daily pharmaceutical dose have been described with reference to the formulation.

[0100] In a further embodiment the pharmaceutical formulation is mucosally administrable to a patient. Preferably the pharmaceutical formulation is provided in the form of a tablet to be swallowed by the patient.

[0101] In a particular embodiment, the therapeutically effective amount of olaparib per dose is in the range 10 to 1000 mg, in a further embodiment the dose comprises 25 to 400 mg of olaparib.

[0102] As used herein, the phrase "therapeutically effective amount" means the drug dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that a therapeutically effective amount of a drug that is administered to a particular subject in a particular instance will not always be effective in treating the conditions / diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art. By way of example, the therapeutically effective amount of olaparib could be 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg or 750 mg e.g. given once or twice a day.

[0103] A typical pharmaceutical formulation provided by the present invention comprises a solid dispersion, comprising olaparib or a salt or a solvate thereof as active ingredient and a polyvinylpyrrolidinon as matrix polymer,

[0104] - wherein the matrix polymer preferably is polyvinylpyrrolidone K15, i.e. has a K-value range from 13 to 19 and has an average molecular weight of 9,700 g / mol, and wherein the polyvinylpyrrolidone K15 preferably has a molecular weight from 6,000 to 15,000 g / mol;

[0105] - wherein the weight ratio of the active agent and the matrix polymer preferably is from 1 : 2.0 to 1 : 3.0;

[0106] - wherein the solid dispersion preferably is a melt extrudate;

[0107] - wherein the formulation preferably comprises an intra- and an extragranular portion, wherein the intragranular portion contains the solid dispersion and wherein the extragranular portion comprises a binder, preferably a hydroxypropyl cellulose (HPC) and / or a hydroxypropylmethyl cellulose, in particular a hydroxypropylmethyl cellulose (HPMC), that in 2 % by weight in water at 20 °C has a viscosity of 4.0 to 6.0 cP, and wherein the extragranular portion preferably further comprises mannitol as a filler; and

[0108] - wherein the pharmaceutical formulation is a tablet. The formulation may find use in a method for increasing the bioavailability of olaparib in a patient in need of said drug, comprising administering to said patient a formulation as de scribed above.

[0109] According to a further aspect of the invention the above”described formulation is for treatment of cancer, for example breast or ovarian cancer, and particularly cancers that possess a defective homologous recombination (HR) dependent DNA double"stranded break (DSB) repair pathway, such as BRCA1+ and / or BRCA2+ve cancers.

[0110] The above-described formulation further is for treatment of prostate cancer, notably in metastatic castrate-resistant prostate cancer (mCRPC).

[0111] According to a further aspect of the invention there is provided a method of producing a solid amorphous dispersion of olaparib comprising :

[0112] (i) mixing a suitable amount of olaparib or a pharmaceutically acceptable salt or solvate thereof with a desired amount of at least one matrix polymer, wherein the matrix polymer comprises polyvinylpyrrolidone;

[0113] (ii) increasing the temperature of the mixture to produce a melt; and

[0114] (iii) extruding the melt to produce a solid dispersion.

[0115] In step (iii) the melt may be extruded as a solid rod which may then be further processed, for example by milling, to produce a powder suitable for use in a pharmaceutical formulation. Alternatively, the melt may be extruded into one or more moulds. Such moulds may, for example provide for shaped products such as elliptical or tablet shapes.

[0116] In step (ii) the melt could be produced by applying thermal heat and / or mechanical stress. According to an embodiment, the solid dispersion of olaparib in a matrix polymer comprising polyvinylpyrrolidone is provided as free flowing powder consisting of micro- or nano-sized primary particles or aggregates thereof.

[0117] To obtain a powder, the extrudate of the solid dispersion obtained in the above-described method may be milled. A suitable particle size after milling is preferably D9o of less than 350 / zm. A desired particle size may be obtained e.g. by sieving or other suitable methods known to the skilled artisan.

[0118] It should be understood that any feature and / or aspect discussed above in connection with the formulation according to the invention apply by analogy to the methods described herein.

[0119] The following figures and examples are provided below to illustrate the present invention. They are intended to be illustrative and are not to be construed as limiting in any way.

[0120] The figures show:

[0121] Figure 1: a graphical representation of in-vitro drug release of olaparib tablets 150 mg comprising different amounts of matrix material;

[0122] Figure 2: a graphical representation of in-vitro drug release of olaparib tablets 150 mg after storage of the tablets;

[0123] Figure 3: an XRD diffraction pattern of a tablet comprising olaparib and a polyvinylpyrrolidone-matrix (povidone K15) in a ratio 1 : 2.4 recorded immediately after production;

[0124] Figure 4: an XRD diffraction pattern of the tablet of Fig. 4 after 1 month storage at 40°C / 75% relative humidity (RH);

[0125] Figure 5: an XRD diffraction pattern of olaparib used for manufacturing the tablets; Figure 6: an XRD diffraction pattern of the tablet of Fig. 6 after 90 days storage at 40°C / 75% relative humidity (RH);

[0126] Figure 7: an XRD diffraction pattern of a tablet comprising olaparib and a polyvinylpyrrolidone-matrix (povidone K30) in a ratio 1 : 2.4 recorded immediately after production;

[0127] Figure 8: an XRD diffraction pattern of the tablet of Fig. 8 after 2 months storage;

[0128] Figure 9: a graphical representation of in-vitro drug release of olaparib tablets 150 mg of RLD (Lynparza®) and formulations T050-240402B-S and T050-240402A-SC.

[0129] Examples

[0130] Materials :

[0131] Olaparib was obtained from a commercial source as a white to off- white solid. Purity was checked by HPLC by comparison of the retention time of the product with a reference olaparib sample.

[0132] Polyvinylpyrrolidone K15 was obtained from Boai NKY Medical Holdings Ltd. as a white to slightly creamy white hygroscopic powder with a K-value of 12.8 - 17.3.

[0133] Example 1: Polyvinylpyrrolidone K15 as matrix polymer

[0134] Olaparib was blended with polyvinylpyrrolidone K15 and colloidal silicon dioxide (glidant) in the proportions defined in table 1. The blend was extruded in a twin-screw extruder. During extrusion, a vacuum was applied to the extruder barrel to degas the melt. The extrudate was calendered by passing through two contra-rotating calender rollers, and then cooled prior to milling. D90of the milled material was less than 350 microns. The milled extrudate was blended with the external excipients as mentioned in table 1 and compressed into tablet form using a single punch hand press to achieve hardness in the range 50-350 N.

[0135] Table 1: Manufacturing of Olaparib Tablets 150 mg by hot melt extrusion (HME) process

[0136] Manufacturing process: Hot melt extrusion by HME machine followed by milling, blending and compression. Based on the formulations of table 1, an optimized formulation was developed. The composition of the optimized formulation is shown in table 2. Two samples were prepared differing in the extragranular material. In a first sample hydroxypropyl-cellulose was used together with mannitol as the extragranular material. In a second sample only mannitol was used. Part of tablets were provided with a coating. Both, coated and uncoated tablets were used in the dissolution tests. For comparison, also a commercially available Olaparib-formulation was examined.

[0137] Table 2: Optimized formulation: Sample analysis

[0138] Dissolution tests:

[0139] Dissolution was carried out in accordance with the general procedure of the United States Pharmacopeia using Apparatus I (Basket method). Tablets obtained in example 1 were placed in

[0140] 900 mL pH 6.8 phosphate buffer at a temperature of 37°C and a stirring speed of 100 rpm. After 15, 30, 45, 60 and 90 minutes a 2 mL sample was removed and the olaparib content determined by HPLC according to conditions summarized in table 3. Table 3: conditions for HPLC analysis

[0141] Dissolution Assay / Related substances:

[0142] The results of the dissolution tests are summarized in table 4.

[0143] Tablet hardness was determined using a Kraemer ELEKTRONIK Hardness tester manufactured by Kraemer Elektronik GmbH according to manufacturer's instructions.

[0144] Table 4: Analytical data obtained for tablets:

[0145] The dissolution profile of the samples is also graphically displayed in Fig. 1. For comparison also the dissolution profile of commercial product (RLD, Lynparza®) is shown in Fig. 9. Stability study

[0146] A study was carried out to examine the physical stability of the amorphous olaparib with respect to solid form conversion or signs of decomposition over time under accelerated storage conditions.

[0147] Coated and uncoated tablets prepared as described in example 1 were packed in Alu -Alu blisters sealed with aluminium foil. The blister packages were stored at 60°C / 75% relative humidity (RH) and at 40°C / 75% RH. After storage time indicated in table 5 a tablet was removed from the blister package and tested for dissolution properties. The corresponding data are summarized in tables 5 and 6. The dissolution behaviour is also displayed in figure 2.

[0148] Table 5: results of stability study (core stage tablets - uncoated)

[0149] Table 6: results of stability tests (coated tablets).

[0150] Recrystallisation of amorphous olaparib

[0151] The sample formulated with API : PVP K15 in a ratio 1 : 2.4 was assessed immediately after preparation and after 3 month, storage at 40°C / 75% RH using XRPD (Model:MiniFlex600, Make: Rigaku) diffractometer; data collection at room temperature using CuKa radiation in the 20 region between 1.5 and 41.5°) . The corresponding XRD diffractograms are displayed in figures 3, 4 and 6. For comparison the XRD diffractogram of amorphous olaparib is displayed in fig. 5.

[0152] The XRD diffractograms of the samples taken immediately after preparation and after 3 months storage at 40°C / 75% RH were similar. Formation of crystalline olaparib was supressed. Example 2: preparation with polj'inyIpyrrolidone K30

[0153] Composition of the formulation is displayed in table 7. Tablets were prepared in a manner corresponding to the method of example 1 wherein, however PVP K30 was used. Table 7: composition of formulation using povidone K30

[0154] Corresponding stress stability tests were performed as described in example 1. Data are summarized in table 8. Table 8: results of stability study (Povidone K30; coated tablets)

[0155]

[0156] Recrystallisation of amorphous olaparib

[0157] The sample formulated with API : PVP K30 in a ratio 1 : 2.4 was assessed immediately after preparation and after 2 month storage at 40°C / 75% RH using XRPD (Model: MiniFlex600, Make: Rigaku) diffractometer; data collection at room temperature using CuKa radiation in the 20 region between 1.5 and 41.5°). The corresponding XRD diffractograms are displayed in figures 7 and 8. For comparison the XRD diffractogram of amorphous olaparib is displayed in fig. 5.

[0158] The XRD diffractograms of the samples taken immediately after preparation and after 2 months storage at 40°C / 75% RH were similar. Formation of crystalline olaparib was supressed. Example 3: further formulations with polyvinylpyrrolidone K15 as matrix polymer

[0159] Compositions of further tablet formulations are displayed in table 9 . These tablets have been prepared in the same way as example 1. Table 9: tablet compositions

Claims

Claims1. A pharmaceutical formulation comprising an active agent in solid, dispersion with a matrix polymer, wherein the active agent is olaparib (4-[3-(4-cyclopropanecarbonyl-piperazine-l- carbonyl)-4-fluoro-benzyl] -2H-phthalazin-l-one) or a salt or solvate thereof, and the matrix polymer comprises polyvinylpyrrolidinon.

2. The formulation as claimed in claim 1, wherein the active agent is in stable amorphous form.

3. The formulation as claimed in any of the preceding claims, wherein the polyvinylpyrrolidone has a K-value of less than 27.

4. The formulation as claimed in any of the preceding claims, wherein the matrix polymer consists of polyvinylpyrrolidone.

5. The formulation as claimed in any of the preceding claims, wherein the matrix polymer is polyvinylpyrrolidone K15.

6. The formulation as claimed in any of the preceding claims, wherein the matrix polymer has a glass transition temperature of less than 145°C.

7. The formulation as claimed in any of the preceding claims, wherein the polyvinylpyrrolidone has a glass transition temperature within a range of 100 to 140°C.

8. The formulation as claimed in any of the preceding claims, wherein the polyvinylpyrrolidone has an average molecular weight Mw within a range of 2500 to 25.000 g / mol.

9. The formulation as claimed in any one of the preceding claims, wherein the ratio of active agent / matrix polymer by weight is from 1 :0.25 to 1 :10.

10. The formulation as claimed in any of the preceding claims, wherein the amount of active agent comprised in the solid dispersion is at least 20 wt.%.

11. The formulation as claimed in any of the preceding claims, wherein the amount of active agent comprised in the formulation (per unit dose) is selected within a range of 10 mg to 1500 mg.

12. The formulation as claimed in any of the preceding claims, wherein the matrix polymer is polyvinylpyrrolidone K15 and the formulation further comprises a glidant, a soluble filler, and a lubricant.

13. The formulation as claimed in any of the preceding claims, wherein the formulation comprises an intra- and an extragranular portion.

14. The formulation as claimed in claim 13, wherein the extragranular portion comprises mannitol as a filler and a binder, preferably hydroxypropyl cellulose (HPC), in particular low-substituted hydroxypropyl cellulose (HPC-L), and / or a hydroxypropylmethyl cellulose (HPMC).

15. The formulation as claimed in claim 14, wherein the amount of hydroxypropyl cellulose (HPC) is between 0% and 6%, preferably between 0.2% and 3%, by weight of the formulation and the amount of hydroxypropylmethyl cellulose (HPMC) is between 0% and 6%, preferably between 0.2% and 3%, by weight of the formulation, wherein the amount of at least one of hydroxypropyl cellulose (HPC) or hydroxypropylmethyl cellulose (HPMC) is more than 0% by weight of the formulation.

16. The formulation as claimed in any of the preceding claims, wherein the solid dispersion is made by melt extrusion.

17. A method of producing a solid amorphous dispersion of olaparib according to any one of claims 1 to 16 comprising:(i) mixing a suitable amount of olaparib or a pharmaceutically acceptable salt or solvate thereof with a desired amount of at least one matrix polymer, wherein the matrix polymer comprises polyvinylpyrrolidone;(ii) increasing the temperature of the mixture to produce a melt; and (iii) extruding the melt to produce a solid product.

18. The method as claimed in claim 17, wherein in step (iii) the melt is extruded into one or more moulds.

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