Fixed dose combination comprising netupitant and palonosetron

Abstract

The present invention relates to a pharmaceutical composition comprising a fixed dose combination of (a) netupitant, or a salt or hydrate thereof, and (b) palonosetron, or a salt or hydrate thereof, in a single pharmaceutical unit. The invention further relates to a method for preparing a pharmaceutical composition in the form of a tablet, the method comprises: (i) wet granulating a dry mixture comprising netupitant or a salt or hydrate thereof, a filler, a binder, a disintegrant, and optionally a surfactant and / or a lubricant, with a solution comprising palonosetron or a salt or hydrate thereof, and optionally a surfactant and / or a binder, to produce granules; (ii) blending the particles with a lubricant, a disintegrant and a glidant, and optionally a filler, and (iii) compacting the lubricated particles to produce a tablet. The invention further relates to the use of said pharmaceutical composition for the treatment and / or prevention of nausea and / or vomiting, preferably for the treatment and / or prevention of acute or delayed nausea and vomiting associated with chemotherapy, such as highly or moderately emetically induced cancer chemotherapy, such as cis-platinum cancer chemotherapy.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical compositions, which include active ingredients of netupitant or its salt or hydrate and palonosetron or its salt or hydrate.

[0002] The present invention relates to a pharmaceutical composition comprising a fixed dose combination of (a) netupitant or a salt or hydrate thereof and (b) palonosetron or a salt or hydrate thereof in a single pharmaceutical unit. The present invention further relates to a method for preparing a pharmaceutical composition in the form of a tablet, the method comprising: (i) wet granulating a mixture comprising netupitant or a salt or hydrate thereof, a filler, a binder, a disintegrant and optionally a surfactant and / or a lubricant with a solution comprising palonosetron or a salt or hydrate thereof and optionally a surfactant and / or a binder to produce granules; (ii) blending the granules with a lubricant, a disintegrant and a glidant and optionally a filler, and (iii) compressing the lubricated granules to produce tablets.

[0003] The present invention further relates to said pharmaceutical composition for use in the treatment and / or prevention of nausea and / or vomiting, preferably in the treatment and / or prevention of acute or delayed nausea and vomiting associated with chemotherapy, such as highly or moderately emetogenic cancer chemotherapy, e.g. cisplatin cancer chemotherapy. Background Art

[0004] Netupitant (INN), chemically known as 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-piperazin-1-yl)pyridin-3-yl]acrylamide (CAS 290297-26-6), is an antinausea and antiemetic agent from the group of substance P / neurokinin 1 (NK-1) receptor antagonists. Netupitant was discovered by Roche and out-licensed to Hesinn Healthcare in 2005.

[0005] Netupitant competitively binds to and blocks the activity of neurokinin 1 (NK-1) receptors in the central nervous system (CNS). Substance P is a neurotransmitter of the neurokinin (tachykinin) family that is present in neurons innervating the nucleus tractus solitarius and area postrema in the brainstem and may be elevated by chemotherapy, leading to nausea and vomiting. By binding to the NK-1 receptor, netupitant inhibits the binding of substance P to the NK-1 receptor and thereby prevents both acute and delayed onset nausea and vomiting during chemotherapy for cancer, for example, the delayed nausea and vomiting phase that occurs after the first 24 hours after chemotherapy administration.

[0006] Palonosetron (INN), chemically known as (3aS)-2-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-3a,4,5,6-tetrahydro-3H-benzo[de]isoquinolin-1-one (CAS 135729-61-2), is commonly used as palonosetron hydrochloride. It is an antinausea and antiemetic agent from the group of serotonin-3 (5-HT3) receptor antagonists. Palonosetron was discovered by Synthex (now part of the Roche Group) and out-licensed to Helsinn Healthcare in 1998.

[0007] Palonosetron acts antagonistically at peripheral and central 5HT3-receptors, preventing serotonin from binding to the receptors, resulting in prevention of serotonin-induced nausea and vomiting, such as the immediate nausea that occurs within the first 24 hours after administration of a chemotherapeutic agent.

[0008] Netupitant and palonosetron are approved by several authorities, including the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), as an oral combination product in the form of hard capsules comprising 300 mg of netupitant and 0.5 mg of palonosetron and are marketed by Helsinn Healthcare SA or its local sales partners. Make sales.

[0009] According to the European Public Assessment Report (EPAR), It is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy and for the prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy. The recommended dose is one capsule taken orally one hour before starting chemotherapy.

[0010] The chemical structure of palonosetron was first described in EP 430 190 B1 (Syntex / Roche). EP 2 099 298 A1 (Helsinn Healthcare) describes amorphous and polymorphic crystalline solid state forms of palonosetron, including Form I and Form II of palonosetron hydrochloride.

[0011] EP 1 035 115 B1 (Roche) first described the chemical structure of netupitant, and EP 1 776 342 B1 (Roche) disclosed the synthesis of netupitant. WO 16 / 46638 A2 (Helsinn Healthcare) describes three crystalline forms of netupitant, including form I of netupitant (as the only disclosed true polymorph) and two pseudo-polymorphs: form II of netupitant (trifluoroethanol solvate) and form III of netupitant (formate salt).

[0012] The commercial formulation is a hard capsule containing netupitant and palonosetron in separate pharmaceutical units within a hard capsule. The hard capsule includes three netupitant tablets as a separate pharmaceutical unit and palonosetron in a soft capsule as another separate pharmaceutical unit. Each netupitant tablet is composed of 100 mg of netupitant, microcrystalline cellulose, sucrose laurate (sucrose laurate), povidone K-30, croscarmellose sodium, colloidal hydrated silicon dioxide, sodium stearyl fumarate, and magnesium stearate. The palonosetron soft capsule is composed of the following: (a) a capsule shell comprising gelatin, glycerol, sorbitol, 1,4-anhydrosorbitan, and titanium dioxide; and (b) a capsule fill comprising 0.5 mg of palonosetron (as the hydrochloride salt, i.e., 0.56 mg of palonosetron hydrochloride), glycerol monocaprylcaproate (Type I), glycerol, polyglycerol oleate, purified water, and butylated hydroxyanisole. Aapro Matti et al. ("NEPA, a fixedoral combination of netupitant and palonosetron, improves control of chemotherapy-induced nausea and vomiting (CINV) over multiple cycles of chemotherapy: results of a randomized, double-blind, phase 3trial versus oralpalonosetron", Supportive Care in Cancer, 2016) described Beneficial effects compared with palonosetron alone in the treatment of patients receiving chemotherapy.

[0013] Business The formulation of palonosetron soft gel capsules is disclosed in EP 1 940 366 B1 (Helsinn Healthcare). EP 2 727 590 B1 discloses The invention provides a dosage form comprising a shell (such as a hard capsule) containing one or more netupitant units (such as a tablet) and one or more palonosetron units (such as a soft gel capsule).

[0014] According to the EPAR, select individual drug units comprising netupitant and palonosetron in a single hard capsule The dosage form is based on the large dose size difference of the active ingredient (300 vs. 0.5 mg) and the difference in the physicochemical properties of netupitant and palonosetron, which makes it difficult to prepare together in a single drug unit. In solid preparations, palonosetron shows reduced efficacy, and netupitant and palonosetron have poor content uniformity. The large dose of 300 mg netupitant further shows insufficient solubility in liquids suitable for filling into soft capsules. Therefore, soft capsules or solid preparations comprising both netupitant and palonosetron cannot be effectively prepared.

[0015] As part of a pharmaceutical combination, a fixed dose combination of netupitant and palonosetron is preferably in the form of , which has also been disclosed in US2018 / 116979, WO 2020 / 068832 A1 and WO 2018 / 039159A1.

[0016] US2018 / 116979 discloses a drug combination comprising memantine (component (a)) and an anticholinergic antiemetic (naAEA, component (b)) for the treatment of hypercholinergic disorders. naAEA may be in the form of The document does not disclose the fixed dose combination of netupitant and palonosetron. any specific alternative formulations and compositions.

[0017] WO 2020 / 068832 A1 discloses a drug combination for treating Parkinson's disease, which includes an inhibitor of adverse reactions of dopamine agonists (AEsI, component (a)) and a dopamine agonist (component (b)). AEsI may include a fixed-dose combination of netupitant and palonosetron. Regarding this fixed-dose combination, reference is made to and US8,951,969 (Helsinn Healthcare), which discloses a method corresponding to The document does not disclose the fixed-dose combination of netupitant / palonosetron. any specific alternative formulations and compositions.

[0018] WO 2018 / 039159 A1 discloses a pharmaceutical composition for treating hypercholinergic disorders, comprising an M2 receptor antagonist (component (a)) and an anticholinergic antiemetic (naAEA, component (b)). naAEA can be an oral fixed-dose combination of netupitant and palonosetron. However, the document does not disclose specific formulations and compositions of the netupitant / palonosetron combination.

[0019] Like in As in commercial preparations of pharmaceutical compositions, the formulation and production of dosage forms including different types of drug units and formulations within one dosage form is generally a complex and time-consuming process, because the different types of drug units need to be manufactured separately by different manufacturing processes and then combined into one dosage form in an additional manufacturing step.

[0020] About Business The formulation and manufacture of soft gel capsules containing palonosetron within the product is typically time consuming and / or requires multiple excipients and often specialized equipment. The manufacturing process for soft gel capsules typically consists of seven major steps, including fill mix preparation (dissolving palonosetron and excipients into the fill solution), gelatin mass preparation, encapsulation into soft gel capsules and lubrication, drying, size sorting, washing, and bulk packaging. The manufacturing process of the netupitant tablets in the product consists of seven major steps, including mixing of netupitant with excipients, high shear wet granulation, drying, grinding, blending with additional excipients, compression and bulk packaging. The entire manufacturing process of hard capsules is a relatively complex and time-consuming manufacturing process.

[0021] In addition, business The product is a large capsule with a length of approximately 22 mm and can lead to poor patient compliance due to the difficulty in swallowing large capsules.

[0022] Difficulty swallowing tablets and capsules can be a problem for many individuals and can lead to various adverse events and patient non-compliance with treatment regimens. It is estimated that more than 16 million people in the United States have swallowing difficulties, also known as dysphagia. For these individuals, swallowing tablets or capsules can be particularly challenging. Surveys of adults with difficulty swallowing tablets and capsules have shown that this problem extends far beyond the patient population of clinically confirmed dysphagia and can affect up to 40% of Americans. Individuals who find it difficult to swallow tablets and capsules often cite size as a major reason for dysphagia.

[0023] The size and shape of tablets and capsules affect the transport of the product through the pharynx and esophagus and can directly affect the patient's ability to swallow a particular drug product. Larger tablets and capsules have been shown to have prolonged esophageal transit times. This can lead to product disintegration in the esophagus and / or cause esophageal damage, resulting in pain and localized esophagitis, as well as potentially serious sequelae including ulcers, strictures, and perforations. Other adverse events, such as pain, nausea, choking, and aspiration, are associated with dysphagia during the oropharyngeal phase of swallowing and occur increasingly with larger tablet and capsule sizes.

[0024] A variety of other factors can affect a patient's ability to swallow tablets or capsules. For example, age can be a factor. Children and adolescents, as well as the elderly, are more likely to have difficulty swallowing tablets or capsules. Body position, fluid intake, and the presence of certain medical conditions can also affect a patient's ability to swallow tablets and capsules.

[0025] Patient compliance with a medication regimen can be affected by the size and shape of the tablet or capsule. Studies in humans have also shown that oval or capsule-shaped tablets are easier to swallow than round tablets of the same weight. The largest dimension of a tablet or capsule should not exceed 22 mm. Generally, it is preferred that the tablet or capsule should not exceed 17 mm in its largest dimension.

[0026] Business The product is a large capsule with a thickness of 7.6 mm and a length of approximately 22 mm, which are the maximum dimensions allowed for an oral product. Given the approved indication for the prevention of nausea and vomiting associated with cancer chemotherapy and the fact that cancer patients often take multiple different drug products daily, patients may often have difficulty swallowing drug products and therefore have reduced compliance, which may be further reduced due to the large capsule size.

[0027] Although combined dosage forms of netupitant and palonosetron are provided, these formulations involve complex, cost-intensive and time-consuming manufacturing processes, including multiple manufacturing steps. In addition, these formulations for oral administration are large in size, which causes difficulty in swallowing and thereby affects patient compliance. Therefore, there is a need to further develop improved and more efficient methods for the formulation of combined pharmaceutical compositions of netupitant and palonosetron that overcome the deficiencies of the prior art, preferably using simplified and reliable compositions and methods to easily manufacture cost-effective and stable formulations having the properties required for the desired medical application. Summary of the Invention

[0028] In view of the prior art, the technical problem underlying the present invention is to provide improved or alternative methods for pharmaceutical compositions comprising a fixed dose combination of netupitant or a salt or hydrate thereof and palonosetron or a salt or hydrate thereof.

[0029] Another object of the present invention is to provide improved or alternative methods for pharmaceutical compositions comprising a fixed dose combination of netupitant, or a salt or hydrate thereof, and palonosetron, or a salt or hydrate thereof, that show comparable or improved solubility and / or oral bioavailability compared to available dosage forms such as hard capsules comprising netupitant tablets and palonosetron soft capsules.

[0030] Another object of the present invention is to provide improved or alternative processes for pharmaceutical compositions comprising a fixed dose combination of netupitant or a salt or hydrate thereof and palonosetron or a salt or hydrate thereof, the manufacture of which is technically reliable, simple and / or cost-effective.

[0031] Another object of the present invention is to provide improved or alternative methods for oral administration of pharmaceutical compositions comprising a fixed dose combination of netupitant, or a salt or hydrate thereof, and palonosetron, or a salt or hydrate thereof, which have good swallowability and better patient compliance compared to available dosage forms. In order to provide a solution to these problems, the present invention seeks to avoid the disadvantages of the prior art.

[0032] These problems are solved by the features of the independent claims. Preferred embodiments of the invention are provided by the dependent claims.

[0033] Thus, one aspect of the present invention relates to a pharmaceutical composition comprising a fixed dose combination of (a) netupitant, or a salt or hydrate thereof, and (b) palonosetron, or a salt or hydrate thereof, in a single pharmaceutical unit.

[0034] Surprisingly, the composition of the present invention includes netupitant and palonosetron in a single pharmaceutical unit, which shows high content uniformity and stability. To the best of the inventors' knowledge, the composition of the present invention represents the first effective pharmaceutical composition of netupitant and palonosetron in admixture (i.e., in a single pharmaceutical unit). Therefore, the provision of the composition of the present invention represents an unexpected technological advancement in the combined formulation of these two APIs.

[0035] To date, the prior art has taught that, due to the processing difficulties associated with the large differences in the dose sizes, physicochemical properties, and content uniformity of the two active pharmaceutical ingredients (APIs), an effective formulation combination of netupitant and palonosetron must be prepared by preparing separate drug units for each API and subsequently combining them into hard capsule shells. This results in a time-consuming and cost-intensive manufacturing process involving multiple steps of preparing drug units for each API and subsequently combining them.

[0036] The composition of the present invention advantageously enables the formulation of netupitant and palonosetron within a single pharmaceutical unit and thus results in a simpler, less complex, cost-effective and technically reliable manufacturing process over the prior art.

[0037] In one embodiment of the present invention, the pharmaceutical composition is in the form of a tablet.

[0038] Surprisingly, compared to the prior art, the composition of the present invention comprising netupitant and palonosetron in a single pharmaceutical unit can be prepared in the form of a solid dosage form such as a tablet. In a preferred embodiment, the tablet of the present invention represents a simple and unexpectedly effective composition considering the difficulties previously reported with the two APIs.

[0039] The prior art teaches that due to the large dose size differences and in particular the differences in physicochemical properties, it has hitherto been impossible to formulate both APIs in a single solid dosage form such as a tablet, since palonosetron exhibits reduced potency and has poor content uniformity, and furthermore, there are no solvents available suitable for dissolving both APIs, thus excluding the formulation of, for example, soft gelatin capsules comprising both APIs within the capsule fill.

[0040] Compared with reference preparation In contrast, the compositions of the present invention comprising a fixed dose combination of netupitant and palonosetron in tablet form have unexpectedly high content uniformity, high stability, and comparable or improved solubility. In addition, the compositions of the present invention show low variability with respect to dissolution and are therefore advantageous with respect to lower variability and the subsequent benefits in absorption and bioavailability of the active ingredients. In contrast, the reference formulation The relatively high dissolution variability exhibited by the present invention can be attributed to the inclusion of the active ingredients in a separate dosage form and the additional packaging of the formulation within a hard capsule shell, which affects the dissolution rate of the dosage form. Therefore, a tablet formulation comprising two APIs in a fixed-dose combination offers the following advantages: a stable formulation with desirable properties for medical use, such as improved dissolution characteristics, while also being easily manufactured, technically reliable, and cost-effective. Given the teachings of the prior art, a skilled artisan would not have anticipated such a combination of improved properties over the prior art.

[0041] In an embodiment, the pharmaceutical composition in tablet form has a size in its longest dimension of no more than 17.5 mm. In an embodiment, the pharmaceutical composition in tablet form has a size in its longest dimension of no more than 17 mm, preferably no more than 15 mm, more preferably no more than 14 mm.

[0042] In an embodiment, the pharmaceutical composition in tablet form has a size in its longest dimension of equal to or less than 17.5 mm. In an embodiment, the pharmaceutical composition in tablet form has a size in its longest dimension of equal to or less than 17 mm, preferably equal to or less than 15 mm, more preferably equal to or less than 14 mm.

[0043] In an embodiment, the tablet has an oval or capsule-shaped form.

[0044] The composition of the present invention advantageously enables the formulation of netupitant and palonosetron in tablets of smaller size than available in the prior art. Thus, the tablets of the present invention offer the advantage of being easier to swallow when administered orally and therefore higher patient compliance.

[0045] Business The product is a large capsule having a length of approximately 22 mm. Since the size and shape of the oral dosage form can directly affect the swallowability and transit of the product through the pharynx and esophagus, and further in view of the indication for the prevention of nausea and vomiting associated with cancer chemotherapy, for Patient compliance may be significantly reduced. In the formulations of the prior art, netupitant and palonosetron need to be formulated in separate pharmaceutical dosage forms, which cannot be effectively packaged in one dosage form, requiring, for example, a large hard capsule shell for packaging. In contrast, in the formulation of the present invention, the active ingredients can be effectively formulated and compressed into one pharmaceutical unit in the form of a tablet, which is significantly smaller, has a lower weight and is easier to swallow than the formulations of the prior art. Therefore, providing the composition of the present invention in the form of a tablet with a smaller size represents an unexpected technical advantage of the prior art, resulting in easier and more reliable intake by patients and therefore higher patient compliance. In one embodiment of the present invention, (a) netupitant or a salt or hydrate thereof and (b) palonosetron or a salt or hydrate thereof are present in the same particulate phase.

[0046] In one embodiment of the present invention, netupitant and palonosetron are present in combination in the intragranular phase.

[0047] The combination of the APIs of the present invention as a blend, in the same granular phase of the composition, is unexpected relative to the prior art. Surprisingly, the two APIs can be prepared in combination, for example using a dry blend comprising netupitant, which is mixed with a liquid comprising palonosetron and granulated, thereby maintaining the two APIs in a single (preferably intragranular) phase. In an embodiment, lubrication of the granules and subsequent tableting enables a simple and effective composition. It would not be expected from the prior art to achieve acceptable content uniformity and solubility of the two APIs from such a composition.

[0048] In one embodiment of the present invention, the composition comprises an intragranular phase comprising a filler, a binder and a disintegrant and optionally a lubricant.

[0049] In one embodiment of the present invention, the filler is microcrystalline cellulose and / or mannitol, the binder is povidone, copovidone and / or corn starch, the disintegrant is cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone and / or pregelatinized starch, and the lubricant is magnesium stearate and / or sodium stearyl fumarate.

[0050] In one embodiment of the present invention, the composition comprises an intragranular phase comprising a surfactant.

[0051] In one embodiment of the present invention, the surfactant is sodium lauryl sulfate (SLS), poloxamer, sucrose laurate, polysorbate 20, polysorbate 80, sorbitan monolaurate and / or sorbitan monooleate.

[0052] In one embodiment of the present invention, the lubricant is magnesium stearate and / or sodium stearyl fumarate, the disintegrant is cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone and / or pregelatinized starch, the glidant is colloidal silicon dioxide, and the filler is microcrystalline cellulose and / or mannitol.

[0053] In one embodiment of the present invention, the pharmaceutical composition does not include titanium dioxide (TiO2).

[0054] Advantageously, the compositions of the present invention do not contain titanium dioxide, as commercial products Titanium dioxide is used as an opacifier and colorant in oral dosage forms such as tablets, granules, hard capsules, and soft gel capsules. However, based on recent safety reviews of titanium dioxide, there are concerns about its genotoxicity. Consequently, the EMA no longer considers titanium dioxide safe as a food additive and it should be avoided or replaced by alternative excipients in pharmaceutical compositions. Therefore, the compositions of the present invention represent a technological advancement over the prior art with respect to avoiding the use of titanium dioxide in combination formulations comprising netupitant and palonosetron.

[0055] In one embodiment of the invention, the pharmaceutical composition does not include animals or products of animal origin. In one embodiment of the invention, the pharmaceutical composition does not include excipients derived from animals. In one embodiment of the invention, the pharmaceutical composition is vegan.

[0056] Advantageously, the compositions of the present invention do not contain excipients of animal origin. In contrast, commercial products The invention relates to a composition comprising several animal-derived excipients, including gelatin from bovine sources in hard capsule shells and shellac in printing inks. Therefore, the composition of the present invention represents a technological advancement that exceeds the prior art with respect to avoiding the use of animal-derived excipients. Therefore, the composition of the present invention is also applicable to vegetarian groups in the world that avoid consuming animal-derived products, which is an increasing proportion. In addition, the vegan formulation is also allowed to be used in patients who follow a Halal or Jewish kosher diet and / or avoid consuming certain animal-derived products for religious reasons. Therefore, compared with the formulations of the prior art, the formulation is conducive to being applied to a larger patient group.

[0057] In one embodiment of the present invention, the pharmaceutical composition comprises an intragranular phase and an extragranular phase, wherein the disintegrant is present in both granular phases, the mass ratio of the disintegrant in the intragranular phase to the disintegrant in the extragranular phase is 5:1 to 1:5, preferably 2:1 to 1:2, more preferably 1:1, and is preferably cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone and / or pregelatinized starch. In one embodiment, the disintegrant is present in both granular phases, preferably the mass ratio of the disintegrant in the intragranular phase to the disintegrant in the extragranular phase is 5:1 to 1:5, such as 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4 or 1:5, more preferably 2:1 to 1:2, more preferably 1:1.

[0058] Surprisingly, compared to prior art formulations In contrast, the compositions of the present invention exhibit beneficial dissolution characteristics. The presence of a disintegrant in both granular phases in combination with the excipients disclosed above enables surprisingly beneficial dissolution, particularly of the typically less soluble API, netupitant. Thus, the disintegrant present in the extragranular phase initially causes the tablet to break up into granules, which in turn further disintegrate due to the intragranular disintegrant portion, resulting in favorable release and dissolution of the active ingredients, netupitant and palonosetron.

[0059] In one embodiment of the present invention, the pharmaceutical composition does not include an antioxidant.

[0060] In one embodiment of the present invention, the pharmaceutical composition comprises: (i) an intragranular combination comprising netupitant or a salt or hydrate thereof, present in an amount of 50-75 wt%, preferably 55-70 wt%, more preferably 58-70 wt%, even more preferably 58-68 wt%; palonosetron or a salt or hydrate thereof, present in an amount of 0.05-0.5 wt%, preferably 0.08-0.3 wt%, more preferably 0.1-0.2 wt%; a filler, present in an amount of 2-40 wt%, preferably 5-35 wt%, more preferably 6-32 wt%; a binder, present in an amount of 0.1-10 wt%, preferably 0.5-9 wt%, more preferably 0.8-8 wt%; a disintegrant, present in an amount of 0.1-5 wt%, preferably 0.5-4 wt%, more preferably 0.8-3.8 wt%; and optionally a surfactant, present in an amount of 0.1-5 wt%, preferably 0. % , preferably 0.5-4 wt %, more preferably 0.8-3.5 wt %; optionally a lubricant in an amount of 0.1-5 wt %, preferably 0.5-3 wt %, more preferably 0.8-1.5 wt %; and (ii) an extragranular component including a lubricant present in an amount of 0.1-5 wt %, preferably 0.5-3 wt %, more preferably 0.8-2.6 wt %, even more preferably 0.8-1.5 wt %; optionally a disintegrant present in an amount of 0.1-5 wt %, preferably 0.5-4 wt %, more preferably 0.8-3.8 wt %; optionally a glidant present in an amount of 0.1-5 wt %, preferably 0.5-3 wt %, more preferably 0.8-2.5 wt %; and optionally a filler in an amount of 1-30 wt %, preferably 5-20 wt %, more preferably 10-15 wt %; wherein the wt % values ​​are based on the total weight of all components of the tablet.

[0061] All values ​​provided above, such as specific preferred values ​​for each component, may vary by + / - 2 wt%, + / - 1 wt%, or + / - 0.5 wt%.

[0062] The following embodiments are also considered to include additional embodiments of the present invention, wherein the indicated amounts of components are employed. These embodiments are not limited by the total weight of the composition, but in some embodiments are limited by the wt% values ​​of each component and / or the presence of each component in the tablet, rather than by absolute weight. For any given characteristic, a preferred weight range in wt% can be employed as a defining characteristic of the composition, without inherently being limited to the specific weights employed in each example or potential combinations with other components in the formulation.

[0063] Embodiments of E1 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0066] Embodiments of E2 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0067] Embodiments of E3 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0068] Embodiments of E4 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0070] Embodiments of E5 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0071] Embodiments of E6 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0073] Embodiments of E7 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0075] Embodiments of E8 based on Netupitant / Palonosetron 300mg / 0.5mg tablets:

[0076] Embodiments of E9 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0078] Embodiments of E10 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0080] Embodiments of E11 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets:

[0081] Embodiments of E12 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0083] Embodiments of E13 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0085] Embodiments of E14 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0086] Embodiments of E15 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0088] Embodiments of E16 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0089] Embodiments of E17 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0090] Embodiments of E18 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0092] Embodiments of E19 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0093] Embodiments of E20 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0095] Embodiments of E21 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0096] Embodiments of E22 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0098] Embodiments of E23 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0100] Embodiments of E24 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0101] Embodiments of E25 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0103] Embodiments of E26 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0104] Embodiments of E27 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0105] Embodiments of E28 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0107] Embodiments of E29 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0108] Embodiments of E30 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0109] Embodiments of E31 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

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[0111] Embodiments of E32 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0112] Embodiments of E33 based on Netupitant / Palonosetron 300mg / 0.5mg tablets:

[0113] Embodiments of E34 based on Netupitant / Palonosetron 300 mg / 0.5 mg tablets:

[0114]

[0115] In one embodiment of the invention, the tablets are uncoated.

[0116] In one embodiment of the present invention, the tablet shows at least 75% dissolution of netupitant after 75 minutes in a dissolution test using USP Apparatus II in 900 ml of 0.07 M phosphate buffer, pH 6.8, containing 1% SDS at a paddle speed of 100 rpm, and / or shows at least 75% dissolution of palonosetron after 45 minutes in a dissolution test using USP Apparatus II in 500 ml of 0.01 N HCl at a paddle speed of 75 rpm.

[0117] In one embodiment of the present invention, the tablets show a content uniformity (CU) of 85% to 115% (based on determination by HPLC analysis) and an acceptable value (AV) of less than 15 for palonosetron according to the content uniformity test of the European Pharmacopoeia (Ph. Eur.) 2.9.40.

[0118] In another aspect, the present invention relates to a pharmaceutical composition as described herein for use in the treatment and / or prevention of nausea and / or vomiting, preferably in the treatment and / or prevention of acute or delayed nausea and vomiting associated with chemotherapy, such as highly or moderately emetogenic cancer chemotherapy, e.g. cisplatin cancer chemotherapy.

[0119] Therefore, the present invention also relates to corresponding methods of treatment and / or prevention, such as a method of treating a subject suffering from nausea and / or vomiting, which comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein.

[0120] In further embodiments, the nausea and / or vomiting is selected from the list of acute or delayed nausea and vomiting associated with chemotherapy, such as highly or moderately emetogenic cancer chemotherapy, for example, cisplatin cancer chemotherapy.

[0121] In another aspect, the present invention relates to a method for preparing a pharmaceutical composition in the form of a tablet, the method comprising: (i) wet granulating a dry mixture comprising netupitant or a salt or hydrate thereof, a filler, a binder, a disintegrant and optionally a surfactant and / or a lubricant with a solution comprising palonosetron or a salt or hydrate thereof and optionally a surfactant and / or a binder to produce granules; (ii) blending the granules with a lubricant, a disintegrant and a glidant and optionally a filler, and (iii) compressing the lubricated granules to produce tablets.

[0122] Advantageously, the pharmaceutical composition of the present invention comprising a fixed dose combination of netupitant and palonosetron can be manufactured in a simple, technically reliable and cost-effective manufacturing process.

[0123] The simple and cost-effective process of the present invention for manufacturing tablets comprising both netupitant and palonosetron involves a single manufacturing process comprising direct granulation of a mixture of netupitant and excipients with a palonosetron solution to produce granules which are subsequently compressed into tablets. A complex and time-consuming process is required because separate and different types of drug units need to be manufactured for netupitant and palonosetron by different manufacturing processes (netupitant tablets and palonosetron soft capsules). Subsequently, these drug units need to be combined into one dosage form in an additional manufacturing step. Therefore, the present invention enables a simpler, less complex and more cost-effective method to manufacture tablets that include both netupitant and palonosetron in a single drug unit, which are comparable and improved in stability, content uniformity and dissolution characteristics relative to prior art formulations.

[0124] The above features regarding the method of making the pharmaceutical composition have structural and functional consequences for the tablets and dispersions of the present invention, such that in some embodiments the tablets and dispersions may be described by features of or derived from the method of making, and vice versa. DETAILED DESCRIPTION

[0125] Netupitant (INN) 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-piperazin-1-yl)pyridin-3-yl]acrylamide (CAS 290297-26-6) and its salts or hydrates are antinausea and antiemetic agents from the group of neurokinin 1 (NK-1) receptor antagonists. Netupitant is a white, non-hygroscopic, crystalline solid that is slightly soluble in water and freely soluble in organic solvents such as acetone, toluene, and methanol.

[0126] The chemical structure of Netupitant is:

[0127]

[0128] Netupitant and its salts or hydrates are selective antagonists of neurokinin 1 (NK-1) receptors. Activation of NK-1 receptors by substance P is associated with nausea and vomiting, particularly delayed nausea and vomiting. These receptors are widely distributed in the central and peripheral nervous systems (CNS and PNS), such as in the gastrointestinal tract (GIT) and the area postrema, as well as in the nucleus of the solitary tract. By reducing and / or inhibiting the binding of substance P to receptors and thereby inhibiting neuronal activation, netupitant prevents acute and delayed onset nausea and vomiting, such as during chemotherapy for cancer.

[0129] Palonosetron (INN)(3aS)-2-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-3a,4,5,6-tetrahydro-3H-benzo[de]isoquinolin-1-one (CAS 135729-61-2) and its salts or hydrates, such as palonosetron hydrochloride, are antinausea and antiemetic agents from the group of serotonin-3 (5-HT3) receptor antagonists. Palonosetron hydrochloride is a white, non-hygroscopic crystalline powder that is soluble in water, slightly soluble in polar organic solvents, and insoluble in most non-polar organic solvents.

[0130]

[0131] The chemical structure of palonosetron is:

[0132] Palonosetron and its salts or hydrates are 5-HT3 receptor antagonists. For example, after the application of chemotherapeutic agents, serotonin (also known as "5-HT") is released from enterochromaffin cells into the small intestine, which is associated with nausea and vomiting due to activation of 5-HT3 receptors on vagal afferents. In addition, activation of vagal afferents may cause serotonin to be released in the area postrema, further promoting vomiting. 5-HT3 receptor antagonists, also known as "setrons," such as palonosetron or its salts or hydrates, inhibit this effect by antagonistically binding to peripheral and central 5-HT3 receptors, thereby reducing or hindering the binding of serotonin to 5-HT3 receptors.

[0133] Netupitant and palonosetron hydrochloride are approved by several authorities, including the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), as a fixed-dose combination containing 300 mg of netupitant and 0.5 mg of palonosetron. Sold by Helsinn Healthcare or its local sales partners.

[0134] Indicated for the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy and for the prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

[0135] Nausea and vomiting are common and atypical symptoms that accompany many diseases. The causes behind them are diverse, including several types of viruses (e.g., rotavirus, adenovirus, coronavirus, and norovirus), bacteria (e.g., Salmonella, Campylobacter, Shigella, Yersinia, Clostridium difficile, and Vibrio cholerae), protozoa (e.g., amebas, giardia), astric diseases, gallbladder disease, chronic pancreatitis, uremia, hepatic coma, vestibular vertigo, Meniere's disease, increased intracranial pressure (e.g., due to previous traumatic brain injury, cerebral hemorrhage, meningitis, and brain tumors), migraine attacks, psychovegetative reactions to visual, olfactory, and auditory stimuli, motion sickness, hyperemesis gravidarum, and vomiting. Nausea and vomiting (e.g., nausea, vomiting ...

[0136] Following administration of chemotherapy (also referred to as "cancer chemotherapy" or "chemotherapeutic agents" or "chemotherapeutic") or radiation therapy, nausea and vomiting may occur immediately within the first 24 hours after administration (acute nausea and / or vomiting) or delayed beyond the first 24 hours after administration (delayed nausea and / or vomiting). Chemotherapeutic agents can be classified according to their emetogenic potential. In the case of combinations of chemotherapeutic agents, the emetogenic potential of the treatment is evaluated based on the most emetogenic chemotherapeutic agent. Highly emetogenic chemotherapeutic agents cause vomiting in >90% of patients and include, but are not limited to, cisplatin, cyclophosphamide (≥1500 mg / m 2 ), streptozotocin, carmustine, dactinomycin, nitrogen mustard, streptozotocin, and dacarbazine. Moderately emetogenic chemotherapeutic agents cause vomiting in 30% to 90% of patients and include, but are not limited to, carboplatin, cyclophosphamide (<1500 mg / m 2), cytarabine, daunorubicin, doxorubicin, epirubicin, endoxane, ifosfamide, oxaliplatin, indarubicin, irinotecan, anthracyclines, azacitidine, oxaliplatin, and bendamustine. Low emetogenic chemotherapeutics cause vomiting in 10% to 30% of patients and include, but are not limited to, etoposide, gemcitabine, 5-fluorouracil (5-FU), docetaxel, paclitaxel, mitomycin, taxanes, cetuximab, bevacizumab, alemtuzumab, catumaxomab, and panitumumab. Mildly emetogenic chemotherapeutics (also referred to as minimally emetogenic chemotherapeutics) cause vomiting in <10% of patients and include, but are not limited to, vinca alkaloids and bleomycin.

[0137] The treatment and / or prevention of nausea and / or vomiting, such as acute and / or delayed nausea and vomiting, associated with chemotherapy, such as highly and / or moderately emetogenic cancer chemotherapy, represents a preferred embodiment of the medical use of the present invention.

[0138] "Administration" or "treatment," as it applies to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, means contacting a drug, therapeutic agent, diagnostic agent, compound, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. "Administration" and "treatment" may refer to, for example, therapeutic agents, placebos, pharmacokinetics, diagnostics, research, and experimental methods. "Treatment," as it applies to humans, veterinary medicine, or research subjects, refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0139] The present invention encompasses administering an effective amount of a chemical substance as described herein to a subject or patient in need thereof. An "effective amount" or "therapeutically effective amount" means an amount that, when administered to a subject or patient, is sufficient to elicit a noticeable biological response, such as an improvement in the symptoms or signs of a disease or physiological condition. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition being treated and the patient's overall health and age. An effective amount can be a maximum dose or a dosing regimen that avoids significant side effects or toxic effects. An "effective amount" also relates to an amount of a substance or pharmaceutical composition thereof that is sufficient to allow or promote a noticeable biological response, such as an improvement in a disease, condition, or pathological state and its symptoms or signs.

[0140] The term "active ingredient" or "API" herein refers to the pharmaceutically active molecules netupitant and / or palonosetron and their pharmaceutically acceptable and / or therapeutically active salts (e.g., palonosetron hydrochloride). The term further refers to pharmaceutically acceptable and therapeutically active hydrates, esters, amides, metabolites, enantiomers, polymorphs, analogs, etc., which induce the desired pharmacological or physiological effects or induce the desired pharmacological or physiological effects after conversion into pharmaceutically active molecules in an organism. Terms such as "active agent", "active pharmaceutical ingredient", "drug substance" can be used synonymously with "active ingredient". The term "pharmaceutically active molecule" herein refers to a molecule that induces a desired pharmacological or physiological effect in an organism and / or a subject. Terms such as "active drug", "active molecule", "therapeutically active molecule", "therapeutically active drug" can be used synonymously with "pharmaceutically active molecule".

[0141] The present invention further relates to salts of netupitant and / or palonosetron. The term "salt" refers to salts prepared by conventional methods, including basic salts of inorganic and organic acids, including, but not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate (also known as ethanesulfonate), fumarate, gluconoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, saccharate, succinate, tartrate, thiocyanate, toluenesulfonate, and undecanoate. For therapeutic use, salts of the compounds are those wherein the counterion is pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0142] The term "excipient" refers to a pharmacologically inactive component of a drug product, such as fillers, lubricants, binders, disintegrants, glidants, flavorings, sweeteners, colorants, film formers, gelling agents, acid regulators, preservatives, absorption enhancers, stabilizers, and the like. Excipients used to prepare pharmaceutical compositions are generally safe, non-toxic, and acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one excipient and more than one excipient.

[0143] In some embodiments, excipients herein are described in terms of "wt%" or "percent by weight" or "% by weight." The %wt values ​​described herein preferably relate to the percentage by weight of the material present in a pharmaceutical composition in tablet form.

[0144] According to the present invention, filler can be used as a filler in solid dosage forms such as tablets and granules. Fillers for tablets include but are not limited to sugars and sugar alcohols such as lactose, sucrose, glucose, mannitol, sorbitol, xylitol, etc., oligosaccharides and polysaccharides such as corn starch, rice starch, potato starch, wheat starch, modified starch derivatives, cellulose, microcrystalline cellulose (MCC), etc., inorganic fillers such as calcium phosphate, calcium hydrogen phosphate, calcium carbonate and mixtures thereof. According to the present invention, preferred fillers are microcrystalline cellulose (MCC) and / or mannitol.

[0145] Microcrystalline cellulose (MCC) is obtained from cellulose by heating with mineral acids and then mechanically pulverizing the cellulose aggregates. Acid treatment causes limited hydrolysis, reducing the degree of polymerization (DP) to about 200-300 and increasing the degree of crystallinity. The dispersion is then spray-dried to produce a powder of agglomerated cellulose microcrystals suitable for direct tablet compression. Microcrystalline cellulose contributes to tablet hardness and reduces the friability of the tablet due to its high plasticity. In addition, tablet compression can be achieved at low compression pressures, resulting in reduced tablet density and therefore fast disintegration and dissolution.

[0146] Mannitol (CAS 69-65-8) is a hexavalent sugar alcohol, the structure of which is derived from mannose and naturally occurs in plants, algae and lichens. In the pharmaceutical industry, mannitol is used as a filler, sweetener and binding agent. Mannitol can be easily compressed and compacted, and is therefore commonly used as a filler to obtain stable small-sized tablets. In the context of the present invention, mannitol is limited to a filler.

[0147] Glidants improve the flow properties of powder mixtures by reducing interparticle friction and therefore also improve dosing accuracy. In particular, highly dispersed silicon dioxide is used as a glidant.

[0148] Silicon dioxide is an oxide of silicon. It is a natural substance, for example found in crystalline form in quartz, granite and sand, and is used in the production of glass. In the pharmaceutical industry, various grades of silicon dioxide are widely used as excipients. Therefore, in particular, highly dispersed silicon dioxide (also called "colloidal silicon dioxide") is used as a flow aid. The production of colloidal or highly dispersed silicon dioxide is carried out by flame hydrolysis of SiCl4, resulting in submicroscopic amorphous spheres with a diameter of about 7-16 nm and a very large surface area of ​​about 200 m 2 / g. Usually, the addition of a small amount of about 0.5% is sufficient to achieve significantly improved flow properties of the powder. According to the present invention, the preferred glidant is colloidal silicon dioxide.

[0149] Disintegrants are excipients used in tablets that cause tablet disintegration, dissolution, and release of the active ingredient upon contact with moisture. Disintegrants can be categorized as substances that increase capillary action, absorb moisture, and swell, compounds that explode with gas release when exposed to moisture, and substances that increase the wettability of the tablet (hydrophilic agents).

[0150] Materials that increase capillary action include soy polysaccharides, alginic acid, cross-linked alginic acid, calcium alginate, sodium alginate, starches such as corn starch, pretreated starches such as pregelatinized starch, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (also known as cross-linked sodium carboxymethylcellulose (croscarmellose sodium)), cross-linked calcium carboxymethylcellulose (also known as carmellose calcium)), cross-linked sodium carboxymethyl starch (also known as sodium starch glycolate), low-substituted hydroxypropyl cellulose (L-HPC) and cross-linked polyvinyl pyrrolidone (also known as crospovidone). The impact of this group is significant in that the applied swelling pressure, the porosity and wettability of the tablet affect water penetration into the tablet, which is a prerequisite for the disintegration process. These disintegrants are highly effective if they have high swelling properties, high swelling pressures and form a pore system with sufficient wettability in the tablet.

[0151] Compared with other disintegrants, high-efficiency disintegrants are more effective at much lower concentrations, with higher disintegration efficiency and mechanical strength, and are referred to as super disintegrants. Super disintegrants include cross-linked sodium carboxymethylcellulose (also known as "croscarmellose sodium"), cross-linked calcium carboxymethylcellulose (also known as "carboxymethylcellulose calcium"), cross-linked sodium starch glycolate (also known as "sodium starch glycolate"), and cross-linked polyvinyl pyrrolidone (also known as "crospovidone"). These water-insoluble substances have high swelling capacity and high capillary activity and ensure spontaneous and complete disintegration without forming mucus.

[0152] Compounds that explode with the release of gas when exposed to moisture include sodium bicarbonate and combinations of bicarbonate with citric or tartaric acid. Tablets with this type of disintegrant disintegrate rapidly due to the release of carbon dioxide during the acidic reaction. These disintegrants are commonly used in oral tablets or effervescent tablets.

[0153] Hydrophilic agents include sodium lauryl sulfate, polysorbate, highly dispersed silicon dioxide and microcrystalline cellulose. Representatives of this group are not technically considered disintegrants per se. Rather, they enable disintegrants to be optimally effective. The tableting of lipophilic substances usually causes considerable difficulties because such tablets have low wettability, so the disintegrants incorporated have no effect or only a very delayed effect. The addition of surfactants (hydrophilic agents) that hydrophilize the tablets ensures that water penetrates the tablet and acts on the incorporated disintegrant.

[0154] According to an embodiment of the present invention, the preferred disintegrant is a super disintegrant, preferably cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone and / or pregelatinized starch.

[0155] Crospovidone (also known as cross-linked polyvinyl N-pyrrolidone, polyvinylpolypyrrolidone or PVPP) is an inert and insoluble white to light yellow free-flowing powder. It has hygroscopic or water-absorbing properties and has excellent swelling characteristics, making it useful as a disintegrant in pharmaceutical dosage forms. Crospovidone is not absorbed orally. Oral use of crospovidone is not generally associated with toxicity in its normal use as a pharmaceutical excipient.

[0156] Sodium starch glycolate is the sodium salt of starch carboxymethyl ether. Starch glycolate is derived from rice, potato, wheat, or corn. Sodium starch glycolate rapidly absorbs water, causing it to swell, which results in rapid tablet disintegration.

[0157] Croscarmellose sodium, also known as "croscarmellose sodium," is the sodium salt of cross-linked carboxymethylcellulose. It is a water-insoluble polysaccharide that swells upon contact with water and is commonly used as a disintegrant in solid dosage forms such as tablets and granules. Croscarmellose sodium is suitable for direct compression tableting and granulation.

[0158] Carboxymethylcellulose calcium, also known as "carboxymethylcellulose calcium" or "CMC calcium," is the calcium salt of a polycarboxymethyl ether of cellulose. It is an effective tablet disintegrant and is used similarly to croscarmellose sodium.

[0159] Pregelatinized starch (PGS) is generally considered a filler (diluent), but may also have some disintegrant-like properties and can therefore be considered a "filler-disintegrant". PGS may also have binder-like properties. Therefore, PGS is a multifunctional excipient. PGS is a starch that has been chemically and / or mechanically processed to rupture all or part of the starch granules. This generally renders the starch flowable and directly compressible (Handbook of Pharmaceutical Excipients (Editor: Rowe)). Partially pregelatinized starch is commercially available. In some embodiments, pregelatinized starch comprises 5% free amylose, 15% free amylopectin and 80% unmodified starch. Pregelatinized starch is typically obtained from maize (corn), potato or rice starch. Pregelatinized starch can be used in granular or tablet formulations and has demonstrated multiple functions as a filler, disintegrant and / or binder. In the context of the present invention, PGS is defined as a disintegrant.

[0160] Lubricant is a kind of excipient added to promote tableting process, particularly about compressed granules. Lubricant can promote the fluidity of granules and / or powder, make it be easily filled into the mold, can reduce the friction between granules and / or powder itself and the friction between mold, punch, granules and powder, and can promote tablet compression and discharge from the mold. Therefore, lubricant can prevent tablet compound and tablet from adhering to the tablet punch and mold. Lubricant for preparing tablets includes magnesium stearate, calcium behenate, glyceryl monostearate, stearic acid, sodium stearyl fumarate, talc, hydrated vegetable fat such as hydrogenated castor oil, hydrogenated cottonseed oil and its mixture. According to the present invention, preferred lubricant is magnesium stearate and / or sodium stearyl fumarate.

[0161] Magnesium stearate (CAS No. 557-04-0) is the magnesium salt of stearic acid and belongs to lime soap. 2+ ) and two stearate groups. Magnesium stearate is insoluble in water. It has a layered crystal structure, resulting in reduced internal friction, and a very small particle size of 3 to 15 μm. Therefore, magnesium stearate is well-suited for use as a lubricant because it adheres to the surfaces of other particles in a powder mixture, reducing inter-particle friction and friction with external surfaces.

[0162] Sodium stearyl fumarate (CAS 4070-80-8) is synthesized by reacting stearyl alcohol with maleic anhydride. The product of this reaction then undergoes an isomerization step before forming a salt to produce sodium stearyl fumarate. Sodium stearyl fumarate is used as a lubricant in oral pharmaceutical formulations and is generally considered to be a non-toxic and non-irritating material.

[0163] According to an embodiment of the present invention, the binding agent holds the ingredients in the tablet together, and is preferably used in the particle during wet granulation. During granulation and for the direct compression of tablets, a binding agent is used to increase the cohesion of powder particles or particles during compression, to ensure that tablets and particles can form a hardness with required mechanical strength and defined. The binding agent can further be used to serve as a processing aid during the granulation process. The binding agent is preferably a macromolecular polar amorphous substance, which exhibits isotropic deformation behavior due to its amorphous nature, and provides optimal conditions for pouring into any available cavity during compression.

[0164] Binders can be classified into natural binders, semi-synthetic polymer binders and synthetic polymer binders. In the context of the present invention, the expression "natural binder" refers to natural polymer binders or their salts or inorganic binders, including starch, processed or pretreated starch or starch salts, such as corn starch, potato starch, sodium starch, pregelatinized starch; alginic acid or its salts, such as sodium alginate; gelatin; guar gum; gum arabic; candelilla wax; carnauba wax, dextran, sugars and hexitols such as lactose, mannitol, sucrose and inorganic calcium compounds such as calcium hydrogen phosphate and tricalcium phosphate.

[0165] In the context of the present invention, the expression "semi-synthetic polymer binder" refers to chemical derivatives of natural polymer binders, including chemical derivatives of cellulose or starch, preferably selected from the group consisting of hydrolyzed starches such as dextran and maltodextrin, hydroxypropyl starch, hydroxypropyl cellulose (HPC, hydroxypropyl cellulose), hydroxypropyl methylcellulose (HPMC, hypromellose), methylcellulose (MC) and sodium carboxymethylcellulose.

[0166] In the context of the present invention, the expression "polymer binder" refers to a completely chemically synthesized non-natural polymer or copolymer binder, preferably selected from the group consisting of polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate, polyethylene glycol graft copolymers (as (sold), polyethylene glycol-polyvinyl alcohol graft copolymer (PEG-PVA), povidone (PVP) and copovidone.

[0167] The binder may be present in the pharmaceutical composition in the form of a single component / ingredient or in the form of a mixture of multiple components / ingredients.Preferred binders according to the present invention are povidone, copovidone and / or corn starch.

[0168] Polyvidone, also known as " polyvinyl pyrrolidone " (PVP), refers to a linear polymer of N-vinyl-2-pyrrolidone (also known as 1-vinyl-2-pyrrolidone). Polyvidone can include polymers having different molecular sizes or chain lengths. Overall, the molecular mass spectrum ranges from 10,000 to 350,000 Da. Povidone typically appears as a white to slightly yellowish-white, highly hygroscopic, odorless powder or flake, and is readily soluble in water and polar organic solvents, such as alcohols, glycols, and glycerol.

[0169] Copolyvidone is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6:4. It has lower hygroscopicity than pyrrolidone and can be used as a binder and film-forming agent for tablet coatings. In the context of the present invention, copolyvidone is defined as a binder.

[0170] According to the present invention, surfactants (surfactants) (also known as surface-active agents, also known as wetting agents, emulsifiers or suspending agents) are substances that adsorb to the surface or interface of a system and reduce the surface tension of the medium in which it is dissolved and / or the interfacial tension with other phases. Surfactants are generally amphiphilic organic compounds, meaning that they have a polar or hydrophilic (i.e., water-soluble) part and a non-polar (i.e., hydrophobic or lipophilic) part. The hydrophobic part of most surfactants is quite similar, consisting of a hydrocarbon chain, which can be branched, straight or aromatic. Surfactant molecules have one tail or two; those with two tails are called double-chain. Most commonly, surfactants are classified according to their hydrophilic part. The hydrophilic group can be anionic, cationic, zwitterionic or nonionic in nature. The principles and applications of surfactants are known to those skilled in the art and are summarized in the literature, for example in the work of Professor Tharwat F. Tadros (Applied Surfactants: Principles and Applications; first published: January 26, 2005; print ISBN: 9783527306299; online ISBN: 9783527604814; DOI: 10.1002 / 3527604812).

[0171] Suitable surfactants according to the present invention may include, but are not limited to, sodium lauryl sulfate (SLS), sucrose laurate, macrogoglycerol ricinoleate (commercially available as EL), polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (respectively as 20, 40, 60 and 80 sales), polyoxyethylene oleic acid glyceryl ester, polyoxyethylene glycol monoether, polyoxyethylene 40 hydrogenated castor oil, polyethoxylated alkyl ether ( 35, 56, 78), Lauroyl Macrogol Glycerides (Gelucire 44 / 14), Polyethoxylated Fatty Acid Esters ( 52. HS15), polyethoxylated glycerides (caprylyl / hexanoyl macrogol glycerides: ), polyoxyethylene castor oil derivatives (polyoxyethylene 35 castor oil: EL, polyoxyethylene polyoxypropylene block copolymers (poloxamers, such as 188. 40. P124 (Poloxamer 124NF / EP)), saturated polyglycol glycerides (lauroyl macrogol glycerides: 44 / 14 (Lauroyl Polyoxyethylene-32 Glycerides), Stearoyl Macrogol Glycerides: 50 / 13), ALF (caprylocaproyl macrogol-8 glyceride), linoleic acid macrogol glycerides, mixed glycerides of long-chain fatty acids (Gelucire 33 / 01), oleic acid, glyceryl monostearate, lecithin, phosphatidylcholine and phosphatidylcholine mixtures (e.g., phosphatidylcholine mixtures in propylene glycol, medium-chain triglycerides, ethanol), unsaturated polyglycolized glycerides (polyglycol glycerides, such as M1944CS, M2125CS), sorbitan esters (such as sorbitan monooleate ( 80) and sorbitan monolaurate ( 20)) and polyethoxylated alkyl ethers 30, 52, 72) and mixtures thereof. According to the present invention, preferred surfactants are sodium lauryl sulfate (SLS, also known as sodium dodecyl sulfate or SDS), poloxamer 188, sucrose laurate (also known as sucrose laurate), polysorbate 20, polysorbate 80, sorbitan monolaurate, sorbitan monooleate or mixtures thereof. The trade names / trademarks disclosed herein have become generally accepted synonyms for the respective chemical compounds, and the chemical names of the respective compounds can also be found by reference to the technical information relating to the respective products.

[0172] The compositions of the present invention may also include other excipients, such as pigments and / or antioxidants, as may be desired.

[0173] Antioxidants are chemical compounds that slow down or completely prevent the oxidation of other substances (e.g., active ingredients or excipients in a pharmaceutical composition). Depending on the type of chemical mechanism of action, antioxidants can be classified as free radical scavengers, reducing agents, and antioxidant synergists. Free radical scavengers are typically compounds with sterically hindered phenolic groups that form inert, stable free radicals that do not react further, resulting in the termination of oxidation reactions. Free radical scavengers include, but are not limited to, tocopherols, tocopheryl acetate, tocotrienols, polyphenolic compounds (e.g., flavonoids, anthocyanins, phytoestrogens, nordihydroguaiaretic acid), carotenoids (e.g., lycopene, β-carotene, and lutein), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and gallic acid esters (e.g., ethyl gallate, propyl gallate, octyl gallate, and dodecyl gallate). Reducing agents have a low redox potential and are therefore more likely to be oxidized than the substance to be protected. Reducing agents include, but are not limited to, ascorbic acid, sulfites, and organic sulfur-containing compounds (e.g., glutathione, cysteine, and thiolactic acid). Antioxidant synergists enhance the effectiveness of antioxidants, e.g., by regenerating depleted antioxidants. Synergists can enhance the antioxidant effect of free radical scavengers or reducing agents by complexing metal traces or generating a pH that inhibits oxidation. Antioxidant synergists include, for example, sodium edetate.

[0174] The most commonly used pharmaceutical solid dosage forms today include granules, pills, tablets and capsules. Tablets are solid pharmaceutical dosage forms containing a drug substance and one or more excipients prepared by compression or molding.

[0175] The method for preparing tablets includes direct compression (direct compression) and granulation (including wet and dry granulation) followed by compression. Tablet compression is carried out by a tablet press, which is a high-speed mechanical device. Two types of tablet presses are mainly used, including eccentric presses and rotary presses. Both have two movable punches (lower punch and upper punch), a die and a hopper per functional unit. These types of tablet presses and their uses are known to those skilled in the art. The present invention preferably includes a method for wet granulation and subsequent tablet production.

[0176] In most cases, the active ingredient and excipients are granulated prior to tableting, converting powder particles into granules. This results in a product with a larger particle size, which has better flow properties compared to powders. This ensures continuous, uniform filling of the tablet press die, resulting in consistent tablet quality and high dosing accuracy. Granules are asymmetric aggregates of powder particles that typically lack a harmonious geometry and have uneven, jagged, or rough surfaces, resulting in good compressibility. Techniques used to prepare granules include wet granulation and dry granulation.

[0177] According to the present invention, wet granulation is a process in which different powder particles are combined together using a binder and / or liquid solution. Wet granulation technology generally involves a granulation liquid, which is preferably a volatile solvent that is easy to remove by drying and should be non-toxic. The choice of liquid depends on the API and other excipients and can be selected as required by the technician. Examples of wet granulation liquids include, for example, water, ethanol, isopropyl alcohol, or any other aqueous solution. The granulation liquid may further include an active pharmaceutical ingredient or an excipient. Various granulation techniques in batch and continuous modes can be used, such as, but not limited to, high shear granulators, fluidized bed granulators, twin-screw granulators, foam granulators, and steam granulators. The process of wet granulation is known to the technician and can be adjusted according to the powder characteristics and available equipment. In a typical wet granulation method, the wet material is forced through a sieve to produce wet granules, which are then dried. The subsequent screening stage breaks up the granule agglomerates. The granules are then pressed into tablets.

[0178] The term "intragranular" or "intragranular phase" refers to the components within the particles or granules of the pharmaceutical composition, i.e., those used to prepare the granular mixture, while the term "extragranular" or "extragranular phase" refers to additives or excipients added to the granules, i.e., additives or excipients added to the intragranular phase after the initial granules are produced.

[0179] As disclosed in the review article "Superdisintegrant: An overview" by Mohanachandran et al. (International Journal of Pharmaceutical Sciences Review and Research, Volume 6, Issue 1, January–February 2011; Article-022), disintegrants used in granular formulation processes can be more effective if used both "intragranularly" and "extragranularly," thereby acting to separate the tablet into granules and further disintegrate the granules to release the drug substance into solution. There are three methods for incorporating disintegrants into tablets: (a) internal addition (intragranular), (b) external addition (extragranular), and (c) in both granular phases (partially internal and external). According to the present invention, the disintegrant is present in the intragranular phase, the extragranular phase or in both granular phases, preferably in a mass ratio of 5:1 to 1:5, such as 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4 or 1:5, more preferably 2:1 to 1:2, more preferably 1:1.

[0180] According to the present invention, the term "drug unit" or "unit" refers to a pharmaceutical composition or mixture comprising one or more active ingredients and one or more excipients, wherein the one or more active ingredients and the one or more excipients are physically present in one phase, such as a powder, a granule, an intragranular phase of a tablet, a tablet, a tablet prepared by compressing granules, a tablet prepared by directly compressing a powder, or a capsule. The drug unit can be in the form of a powder, granules, pills, tablets, or soft capsules, for example. In an embodiment, the drug unit can be directly administered to a subject as a dosage form, or further processed to form a dosage form for administration to a subject, such as compressing granules into tablets. In an embodiment, the drug unit is a final dosage form suitable for administration to a subject. In an embodiment, the drug unit is a granule, i.e., a single particle phase. According to the present invention, the active ingredients netupitant and palonosetron or a salt or hydrate thereof are present in a single drug unit, preferably in a granule, more preferably in the intragranular phase of a tablet prepared by compressing granules.

[0181] The terms "fixed dose" and "fixed dose combination" refer to pharmaceutical compositions comprising defined amounts of one or more active ingredients within one pharmaceutical unit or dosage form. In an embodiment, a fixed dose combination is a combination of two or more final dosage forms suitable for direct administration to a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0182] The present invention is illustrated with the aid of the accompanying drawings disclosed herein, which provide support for a detailed description of possible preferred non-limiting embodiments of the present invention.

[0183] Figure 1 : For Example E2 and Reference Product Comparative dissolution of Netupitant measured.

[0184] Figure 2 : For Example E2 and Reference Product Comparative dissolution of palonosetron hydrochloride measured.

[0185] Figure 3 : For Example E3 and Reference Product Comparative dissolution of Netupitant measured.

[0186] Figure 4 : For Example E3 and Reference Product Comparative dissolution of palonosetron hydrochloride measured.

[0187] Figure 5 : For Example E30 and Reference Product Comparative dissolution of Netupitant measured.

[0188] Figure 6 : For Example E30 and Reference Product Comparative dissolution of palonosetron hydrochloride measured.

[0189] Figure 7 : Photograph of a tablet prepared according to Example E2. The tablet has a weight of 450 mg, a thickness of 6.09 to 6.16 mm, a width of 7.5 mm and a length of 14 mm.

[0190] Figure 8 : For Example E31 and Reference Product Comparative dissolution of Netupitant measured.

[0191] Figure 9 : For Example E31 and Reference Product Comparative dissolution of palonosetron hydrochloride measured.

[0192] Figure 10 : For Example E32 and Reference Product Comparative dissolution of Netupitant measured.

[0193] Figure 11 : For Example E32 and Reference Product Comparative dissolution of palonosetron hydrochloride measured.

[0194] Figure 12 : For Example E33 and Reference Product Comparative dissolution of Netupitant measured.

[0195] Figure 13 : For Example E33 and Reference Product Comparative dissolution of palonosetron hydrochloride measured.

[0196] Example

[0197] The present invention is demonstrated with the aid of the examples disclosed herein. The examples provide technical support for a detailed description of possible preferred non-limiting embodiments of the present invention.

[0198] Part A - General Manufacturing Procedures

[0199] General Manufacturing Procedure (GP1) using wet granulation process:

[0200] 1. Distribution:

[0201] 1.1. Allocate all materials according to the materials list.

[0202] 2. Screening:

[0203] 2.1. Co-sieving stage - A material passed ASTM #20 mesh.

[0204] 3. Preparation of API solution:

[0205] 3.1. Dissolve Phase-B materials in purified water.

[0206] 4. Granulation:

[0207] 4.1. Granulate the material from step 2.1 with the API solution from step 3.1 using a rapid mixing granulator.

[0208] 5. Drying:

[0209] 5.1. Use a quick dryer to dry the material in step 4.1.

[0210] 6. Grinding:

[0211] 6.1. Grind the material from step 5.1 using a quadro co mill equipped with a 40G sieve.

[0212] 7. Screening of additional granular material:

[0213] 7.1. Sieve the Stage-C material using ASTM #35 mesh.

[0214] 8. Blending:

[0215] 8.1. Blend the materials from step 6.1 and step 7.1 using a suitable blender.

[0216] 9. Suppression:

[0217] 9.1. Compact the blend lubricated in step 8.1 using a suitable punch.

[0218] General Manufacturing Procedure (GP2) using dry granulation process:

[0219] 1. Distribution:

[0220] 1.1. Allocate all materials according to the materials list.

[0221] 2. Screening:

[0222] 2.1. Co-screening of Palonosetron HCl 1H and microcrystalline cellulose ( 102) Pass ASTM #30 mesh.

[0223] 3. Blending:

[0224] 3.1. Blend the materials from step 2.1 using a suitable blender.

[0225] 4. Screening:

[0226] 4.1. Co-sieve step 3.1 and stage-B materials through ASTM #20 mesh.

[0227] 5. Blending:

[0228] 5.1. Blend the materials from step 4.1 using a suitable blender.

[0229] 6. Dry granulation:

[0230] 6.1. Granulate the material from step 5.1 using a Chilsonator with appropriate parameters.

[0231] 7. Grinding:

[0232] 7.1. Grind the material from step 6.1 using an OG grinder or Chilsonator grinder equipped with a 1.0 mm screen.

[0233] 8. Screening of additional granular material:

[0234] 8.1. Sieve the Stage-C material using ASTM #35 mesh.

[0235] 9. Blending:

[0236] 9.1. Blend the materials from step 6.1 and step 5.1 using a suitable blender.

[0237] 10. Suppression:

[0238] 10.1. Compact the blend lubricated in step 7.1 using a suitable punch.

[0239] General Manufacturing Procedure (GP3) using direct pressing process:

[0240] 1. Distribution:

[0241] 1.1. Allocate all materials according to the materials list.

[0242] 2. Screening:

[0243] 2.1. Co-screening of Palonosetron HCl IH and Microcrystalline Cellulose 102) through ASTM #30 mesh and re-screened through ASTM #30 mesh.

[0244] 3. Blending:

[0245] 3.1. Blend the materials from step 2.1 using a suitable blender.

[0246] 4. Grinding:

[0247] 4.1. Co-grind the materials from step 3.1 and stage-B through the screen of an appropriate co-grinding machine.

[0248] 5. Blending:

[0249] 5.1. Blend the materials from step 4.1 using a suitable blender.

[0250] 6. Screening:

[0251] 6.1. Sieve magnesium stearate using ASTM #35 mesh.

[0252] 7. Blending:

[0253] 7.1. Blend the materials from step 6.1 and step 5.1 using a suitable blender.

[0254] 8. Suppression:

[0255] 8.1. Compact the blend lubricated in step 7.1 using a suitable punch.

[0256] Part B - Examples of the Invention

[0257] Examples E1 to E24 and E27 to E34 were prepared according to General Procedure GP1. Example E25 was prepared according to General Procedure GP2. Example E26 was prepared according to General Procedure GP3.

[0258] Example E1 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API and sodium lauryl sulfate as the surfactant by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0259]

[0260] Example E2 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as APIs and poloxamer 188 as a surfactant by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0261]

[0262] Example E3 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API by wet granulation. The binder, povidone, is placed in the intragranular phase and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0263]

[0264]

[0265] Example E4 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API and sodium lauryl sulfate as the surfactant by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0266]

[0267] Example E5 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API and sodium lauryl sulfate as the surfactant by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0268]

[0269] Example E6 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API and sodium lauryl sulfate as the surfactant by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0270]

[0271]

[0272] Example E7 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API and sodium lauryl sulfate as the surfactant by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0273]

[0274]

[0275] Example E8 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API and sodium lauryl sulfate as the surfactant by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0276]

[0277] Example E9 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs and microcrystalline cellulose and mannitol as fillers (at a 50:50 weight ratio) as tablets, prepared by wet granulation. The binder, povidone, is placed in the intragranular phase and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases at a 50:50 weight ratio.

[0278]

[0279] Example E10 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs and microcrystalline cellulose and mannitol as fillers (in a 1:3 weight ratio) as tablets, prepared by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0280]

[0281]

[0282] Example E11 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs and microcrystalline cellulose and mannitol as fillers (in a 3:1 weight ratio) as tablets, prepared by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0283]

[0284]

[0285] Example E12 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs and microcrystalline cellulose and mannitol as fillers (in a 50:50 weight ratio) as tablets, prepared by wet granulation. The binder, povidone, is placed in the intragranular phase and the disintegrant, croscarmellose sodium, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio. Lower concentrations of the binder, povidone, and the surfactant, sodium lauryl sulfate, are used.

[0286]

[0287]

[0288] Example E13 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablet: The composition of the present invention comprises netupitant and palonosetron as API and polysorbate 20 ( 20) as a surfactant, prepared by wet granulation. The binder povidone is placed in the granule inner phase and the disintegrant croscarmellose sodium is distributed in the granule inner phase and the granule outer phase in a 50:50 weight ratio. The surfactant is placed in the binder solution.

[0289]

[0290] Example E14 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablet: The composition of the present invention comprises netupitant and palonosetron as API and polysorbate 80 ( 80) as a surfactant, prepared by wet granulation. The binder povidone is placed in the granular inner phase and the disintegrant croscarmellose sodium is distributed in the granular inner phase and the granular outer phase in a 50:50 weight ratio. The surfactant is placed in the binder solution.

[0291]

[0292] Example E15 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablet: The composition of the present invention comprises Netupitant and Palonosetron as API and Sorbitan Monolaurate ( 20) as a surfactant, prepared by wet granulation. The binder povidone is placed in the granule inner phase and the disintegrant croscarmellose sodium is distributed in the granule inner phase and the granule outer phase in a 50:50 weight ratio. The surfactant is placed in the binder solution.

[0293]

[0294]

[0295] Example E16 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises Netupitant and Palonosetron as APIs and Sorbitan Monooleate ( 80) as a surfactant, prepared by wet granulation. The binder povidone is placed in the granular inner phase and the disintegrant croscarmellose sodium is distributed in the granular inner phase and the granular outer phase in a 50:50 weight ratio. The surfactant is placed in the binder solution.

[0296]

[0297]

[0298] Example E17 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising Netupitant and Palonosetron as APIs and sodium lauryl sulfate as a surfactant by wet granulation. The binder, povidone, is placed in the inner granular phase, and the disintegrant, croscarmellose sodium, is placed in the outer granular phase.

[0299]

[0300] Example E18 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API and sodium lauryl sulfate as a surfactant by wet granulation. The binder, povidone, and the disintegrant, croscarmellose sodium, are placed in the intragranular phase.

[0301]

[0302] Example E19 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API, sodium lauryl sulfate as a surfactant, and sodium starch glycolate as a disintegrant by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, sodium starch glycolate, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0303]

[0304]

[0305] Example E20 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises Netupitant and Palonosetron as APIs and sodium lauryl sulfate as a surfactant and crospovidone type A ( XL) as disintegrant, prepared by wet granulation. The binder povidone was placed in the granule inner phase and the disintegrant crospovidone type A ( XL) is distributed in the intragranular phase and the extragranular phase in a 50:50 weight ratio.

[0306]

[0307]

[0308] Example E21 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API, sodium lauryl sulfate as a surfactant, and pregelatinized starch as a disintegrant by wet granulation. The binder, povidone, is placed in the intragranular phase, and the disintegrant, pregelatinized starch, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0309]

[0310] Example E22 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as the API and sodium lauryl sulfate as the surfactant, as a tablet, prepared by wet granulation. The binder, povidone, is distributed in the intragranular and extragranular phases in a 50:50 weight ratio.

[0311]

[0312]

[0313] Example E23 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, and copovidone as a binder, as a tablet prepared by wet granulation. The binder, povidone, is placed in the inner phase of the granules.

[0314]

[0315]

[0316] Example E24 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, and corn starch as a binder as a tablet, prepared by wet granulation. The binder, povidone, is placed in the inner phase of the granules.

[0317]

[0318]

[0319] Example E25 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention as a tablet comprises Netupitant and Palonosetron as APIs, sodium lauryl sulfate as a surfactant, and corn starch as a binder, and is prepared by dry granulation.

[0320]

[0321] Example E26 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs and sodium lauryl sulfate as surfactant and corn starch as binder as tablets prepared by direct compression.

[0322]

[0323]

[0324] Example E27 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising netupitant and palonosetron as the API, sodium lauryl sulfate as a surfactant, and sodium stearyl fumarate as a lubricant by wet granulation. The lubricant, sodium stearyl fumarate, is distributed in a 50:50 weight ratio between the intragranular phase and the extragranular phase.

[0325]

[0326] Example E28 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention is prepared as a tablet comprising Netupitant and Palonosetron as APIs, sodium lauryl sulfate as a surfactant, and sodium stearyl fumarate and magnesium stearate as lubricants by wet granulation. The lubricant sodium stearyl fumarate is placed in the inner granular phase and the lubricant magnesium stearate is placed in the outer granular phase.

[0327]

[0328] Example E29 of Netupitant / Palonosetron 300mg / 0.5mg Tablets: The composition of the present invention comprises, as a tablet, Netupitant and Palonosetron as API, Polysorbate 80 ( 80) as a surfactant, mannitol and microcrystalline cellulose as fillers, and sodium stearyl fumarate as a lubricant were prepared by wet granulation. The filler mannitol was placed in the intragranular phase and the filler microcrystalline cellulose was placed in the extragranular phase. The lubricant sodium stearyl fumarate was placed in the extragranular phase.

[0329]

[0330]

[0331] Example E30 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, sodium stearyl fumarate and magnesium stearate as lubricants, and microcrystalline cellulose and mannitol as fillers (25:75 weight ratio) as tablets, prepared by wet granulation. The lubricant sodium stearyl fumarate is placed in the inner granular phase and the lubricant magnesium stearate is placed in the outer granular phase.

[0332]

[0333]

[0334] Example E31 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, sodium stearyl fumarate and magnesium stearate as lubricants, and microcrystalline cellulose and mannitol as fillers (50:50 weight ratio) as tablets, prepared by wet granulation. The lubricant sodium stearyl fumarate is placed in the inner granular phase and the lubricant magnesium stearate is placed in the outer granular phase.

[0335]

[0336]

[0337] Example E32 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, sodium stearyl fumarate and magnesium stearate as lubricants, and microcrystalline cellulose and mannitol as fillers (75:25 weight ratio) as tablets, prepared by wet granulation. The lubricant sodium stearyl fumarate is placed in the inner phase of the granules, and the lubricant magnesium stearate is placed in the outer phase of the granules.

[0338]

[0339] Example E33 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, sodium stearyl fumarate and magnesium stearate as lubricants, and microcrystalline cellulose and mannitol as fillers (23:77 weight ratio) as tablets, prepared by wet granulation. The lubricant sodium stearyl fumarate is placed in the inner granular phase and the lubricant magnesium stearate is placed in the outer granular phase.

[0340]

[0341] Example E34 of Netupitant / Palonosetron 300 mg / 0.5 mg Tablets: The composition of the present invention comprises netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, sodium stearyl fumarate and magnesium stearate as lubricants, and microcrystalline cellulose and mannitol as fillers (50:50 weight ratio) as tablets, prepared by wet granulation. The lubricant sodium stearyl fumarate is placed in the inner granular phase and the lubricant magnesium stearate is placed in the outer granular phase.

[0342]

[0343]

[0344] For compression of tablets according to Examples E1 to E34, the tooling used was a 14.0 X 7.5 or 15.0 X 7.0 oval shape.

[0345] The resulting tablets had dimensions of 14 mm x 7.5 mm or 15 mm x 7 mm, respectively, and a thickness of 4.5-6.8 mm.

[0346] Part C - Reference Product Characterization

[0347] surface: Reference products Physical parameters of 300mg / 0.5mg capsules

[0348]

[0349] Part D - Dissolution Study

[0350] Dissolution testing was performed using US Pharmacopoeia (USP) Apparatus II (Paddles) and following the following method as recommended for the combination of netupitant and palonosetron hydrochloride in the FDA Dissolution Method Database on the FDA webpage:

[0351] Netupitant: 900 ml of 0.07 M phosphate buffer, pH 6.8, containing 1% SDS (SLS) and a paddle speed of 100 revolutions per minute (rpm), with 75 minutes as the QC sampling time.

[0352] Palonosetron Hydrochloride: 500 ml of 0.01 N HCl with a paddle speed of 75 rpm and a QC sampling time of 45 minutes.

[0353] surface: Dissolution profile of 300 / 0.5 mg (Batch No. 41000954) in 0.07 M sodium phosphate buffer, pH 6.8, containing 1% SDS – Netupitant

[0354]

[0355] surface: Dissolution characteristics of 300 / 0.5 mg (Batch No.: 41000954) in 0.01 N HCl - Palonosetron

[0356]

[0357] Table: Dissolution profile of E2 of Netupitant / Palonosetron 300 mg / 0.5 mg tablets in pH 6.8 0.07 M sodium phosphate buffer containing 1% SDS - Netupitant

[0358]

[0359] for For the tablets of Example E2 and Example E3, complete release of netupitant was observed after 75 minutes, with more than 95% of the drug released.

[0360] According to the FDA guidance "Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on abiopharmaceutics classification system," dissolution results are considered highly variable if the relative standard deviation (RSD) exceeds 20% at a time point of 10 minutes or less and exceeds 10% at later time points.

[0361] The netupitant dissolution results at pH 6.8 showed high variability up to 30 minutes, while inventive example E2 exhibited low variability.

[0362] Table: Dissolution profile of E2 of Netupitant / Palonosetron 300 mg / 0.5 mg tablets in 0.01 N HCl - Palonosetron

[0363]

[0364] for For the tablets of Example E2 and Example E3, complete release of palonosetron was observed after 45 minutes, with more than 95% of the drug released.

[0365] The results for the dissolution of palonosetron in 0.01 N HCl medium showed very high variability up to 15 minutes, whereas inventive example E2 exhibited low variability.

[0366] Table: Dissolution profile of Netupitant / Palonosetron 300 mg / 0.5 mg tablet E3 in pH 6.8 0.07 M sodium phosphate buffer containing 1% SDS - Netupitant

[0367]

[0368]

[0369] for Tablets of Example E3 and Example E3 showed complete release of netupitant after 75 minutes, with more than 95% of the drug released. The dissolution of Example E3 showed low variability. Table: Dissolution profile of netupitant / palonosetron 300 mg / 0.5 mg tablets E3 in 0.01 N HCl - Palonosetron

[0370]

[0371] for Tablets of Example E3 and Example E3 showed complete release of palonosetron after 45 minutes, with more than 95% of the drug released. The dissolution of Example E3 exhibited low variability. Table: Dissolution profile of Netupitant / Palonosetron 300 mg / 0.5 mg tablets E30 in pH 6.8 0.07 M sodium phosphate buffer containing 1% SDS - Netupitant

[0372]

[0373]

[0374] for Tablets of Example E30 and Example E30 showed complete release of netupitant after 75 minutes, with more than 95% of the drug released. The dissolution of Example E30 showed low variability. Table: Dissolution profile of netupitant / palonosetron 300 mg / 0.5 mg tablets of Example E30 in 0.01 N HCl - Palonosetron

[0375]

[0376] for For the tablets of Example E30, complete release of palonosetron was observed after 45 minutes, with more than 95% of the drug released. The dissolution of Example E30 exhibited low variability.

[0377] Table: Dissolution profile of Netupitant / Palonosetron 300 mg / 0.5 mg tablet E31 in pH 6.8 0.07 M sodium phosphate buffer containing 1% SDS - Netupitant

[0378]

[0379]

[0380] for With the tablets of Example E31, complete release of netupitant was observed after 75 minutes, with more than 95% of the drug released. In comparison, the dissolution of Example E31 showed lower variability.

[0381] Table: Dissolution profile of Netupitant / Palonosetron 300 mg / 0.5 mg tablet Example E31 in 0.01 N HCl - Palonosetron

[0382]

[0383] for For the tablets of Example E31, complete release of palonosetron was observed after 45 minutes, with more than 95% of the drug released. The dissolution of Example E31 exhibited low variability.

[0384] Table: Dissolution profile of Netupitant / Palonosetron 300 mg / 0.5 mg tablet E32 in pH 6.8 0.07 M sodium phosphate buffer containing 1% SDS - Netupitant

[0385]

[0386]

[0387] for With the tablets of Example E32, complete release of netupitant was observed after 75 minutes, with more than 95% of the drug released. In comparison, the dissolution of Example E32 showed lower variability.

[0388] Table: Dissolution profile of Netupitant / Palonosetron 300 mg / 0.5 mg tablet Example E32 in 0.01 N HCl - Palonosetron

[0389]

[0390] for For the tablets of Example E32, complete release of palonosetron was observed after 45 minutes, with more than 95% of the drug released. The dissolution of Example E32 exhibited low variability.

[0391] Table: Dissolution profile of Netupitant / Palonosetron 300 mg / 0.5 mg tablet E33 in pH 6.8 0.07 M sodium phosphate buffer containing 1% SDS - Netupitant

[0392]

[0393]

[0394] for With the tablets of Example E33, complete release of netupitant was observed after 75 minutes, with more than 95% of the drug released. In comparison, the dissolution of Example E33 showed lower variability.

[0395] Table: Dissolution profile of Netupitant / Palonosetron 300 mg / 0.5 mg tablet Example E33 in 0.01 N HCl - Palonosetron

[0396]

[0397] for For the tablets of Example E33, complete release of palonosetron was observed after 45 minutes, with more than 95% of the drug released. The dissolution of Example E33 exhibited low variability.

[0398] In the corresponding quality control (QC) dissolution media, all formulations of Examples E2, E3, E30, E31, E32 and E33 of the present invention showed a dissolution rate of not less than 75% for netupitant after 75 minutes and a dissolution rate of not less than 75% for palonosetron hydrochloride after 45 minutes, and met the regulatory standard QC test. The dissolution rates of the formulations of the present invention were comparable to those of the commercially available reference product. Comparable.

[0399] The dissolution results of netupitant at pH 6.8 showed high variability up to 30 minutes, while the dissolution of the formulations of the present invention E2, E3, E30, E31, E32 and E33 showed similar dissolution rates to those of the formulations of the present invention. Lower variability in drug release compared to netupitant. The dissolution results of palonosetron in 0.01 N HCl medium showed very high variability up to 15 minutes, whereas the dissolution of the formulations of the present invention E2, E3, E30, E31, E32 and E33 demonstrated low variability in palonosetron drug release.

[0400] Content uniformity of some E-palonosetron

[0401] The content uniformity of the tablets according to the invention was evaluated using formulations according to Examples E1, E2 and E32.

[0402]

[0403] As can be observed from the data presented above, the content uniformity of palonosetron within the formulations according to the present invention was found to be within the specification limits according to European Pharmacopoeia 2.9.40. To ensure consistency of dosage units, each unit in a batch should have an active substance content within a narrow range around the label claim. A dosage unit is defined as a dosage form containing a single dose or part dose of active substance in each dosage unit. The term "uniformity of a dosage unit" is defined as the degree of uniformity of the amount of active substance between dosage units. Therefore, the requirements of this rule are applicable to any active substance included in a dosage unit containing one or more active substances. The uniformity of the dosage form (by content uniformity) is evaluated according to European Pharmacopoeia 2.9.40.

[0404] According to the reference product The EPAR of the present invention was not significantly different from that of the co-formulation of netupitant and palonosetron within a single solid dosage form, which had poor content uniformity, particularly due to the large difference in the dose size of the active ingredients (300 vs. 0.5 mg) and the differences in the physicochemical properties of netupitant and palonosetron. The invention provides an improvement in the formulation as the formulation shows high content uniformity and enables co-formulation of netupitant and palonosetron within a single solid pharmaceutical unit.

[0405] Part F-stability study:

[0406] According to ICH guideline Q1A(R2), bulk formulations were packaged in Alu-Alu blisters and stored at 40°C / 75% RH (ICH accelerated conditions) and 25°C / 60% RH (ICH long-term conditions) for 6 months.

[0407] Netupitant and palonosetron were initially tested for related substances (impurities and / or degradation products) before storage and after storage under the conditions shown in the tables of the corresponding examples. Related substances were detected by HPLC analysis.

[0408] Table: Related substance data of Netupitant and Palonosetron 300 / 0.5 mg tablets (Example E1)

[0409]

[0410] Table: Related substance data of Netupitant and Palonosetron 300 / 0.5 mg tablets (Example E2)

[0411]

[0412] As can be observed from the above table, the novel formulation of the present invention showed high stability in Alu-Alu blisters after 6 months under ICH long-term conditions (25°C / 60% RH) and under ICH accelerated conditions (40°C / 75% RH).

Claims

1. A pharmaceutical composition comprising a fixed dose combination of (a) netupitant or a salt or hydrate thereof and (b) palonosetron or a salt or hydrate thereof in a single pharmaceutical unit.

2. The pharmaceutical composition according to claim 1, in the form of a tablet.

3. A pharmaceutical composition according to any one of the preceding claims, wherein The (a) netupitant or its salt or hydrate and (b) palonosetron or its salt or hydrate exist in the same particulate phase.

4. The pharmaceutical composition according to claim 3, wherein The netupitant and the palonosetron are present in combination in the intragranular phase.

5. A pharmaceutical composition according to any one of the preceding claims, wherein The composition comprises an intragranular phase comprising a filler, a binder and a disintegrant and optionally a lubricant.

6. The pharmaceutical composition according to claim 5, wherein The filler is microcrystalline cellulose and / or mannitol, the binder is povidone, copovidone and / or corn starch, the disintegrant is cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone and / or pregelatinized starch, and the lubricant is magnesium stearate and / or sodium stearyl fumarate.

7. A pharmaceutical composition according to any one of the preceding claims, wherein The composition includes an intragranular phase comprising a surfactant.

8. The pharmaceutical composition according to claim 7, wherein The surfactant is sodium lauryl sulfate (SLS), poloxamer 188, sucrose laurate, polysorbate 20, polysorbate 80, sorbitan monolaurate and / or sorbitan monooleate.

9. A pharmaceutical composition according to any one of the preceding claims, wherein The composition comprises an extragranular phase comprising a lubricant, a disintegrant and a glidant and optionally a filler.

10. The pharmaceutical composition according to claim 9, wherein The lubricant is magnesium stearate and / or sodium stearyl fumarate, the disintegrant is cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone and / or pregelatinized starch, the glidant is colloidal silicon dioxide, and the filler is microcrystalline cellulose and / or mannitol.

11. The pharmaceutical composition according to any one of the preceding claims, comprising an intragranular phase and an extragranular phase, wherein the disintegrant is present in both granular phases, the mass ratio of disintegrant in the intragranular phase to disintegrant in the extragranular phase is 5:1 to 1:5, preferably 2:1 to 1:2, more preferably 1:1, and is preferably croscarmellose sodium, sodium starch glycolate, crospovidone and / or pregelatinized starch.

12. A pharmaceutical composition according to any one of the preceding claims which does not comprise an antioxidant.

13. A pharmaceutical composition according to any one of the preceding claims, comprising i. Intra-particle combination, including: a) Netupitant or a salt or hydrate thereof, present in an amount of 50-75 wt%, preferably 55-70 wt%, more preferably 58-68 wt%, b) palonosetron or a salt or hydrate thereof, present in an amount of 0.05-0.5 wt%, preferably 0.08-0.3 wt%, more preferably 0.1-0.2 wt%, c) filler, present in an amount of 2-40 wt%, preferably 5-35 wt%, more preferably 6-32 wt%, d) Binder, present in an amount of 0.1-10 wt%, preferably 0.5-9 wt%, more preferably 0.8-8 wt% e) a disintegrant, present in an amount of 0.1-5 wt%, preferably 0.5-4 wt%, more preferably 0.8-3.8 wt%, f) optionally a surfactant in an amount of 0.1-5 wt%, preferably 0.5-4 wt%, more preferably 0.8-3.5 wt%, g) optionally a lubricant in an amount of 0.1-5 wt%, preferably 0.5-3 wt%, more preferably 0.8-1.5 wt%, as well as ii. Extragranular components, including: a) a lubricant, present in an amount of 0.1-5 wt%, preferably 0.5-3 wt%, more preferably 0.8-1.5 wt%, b) optionally a disintegrant, present in an amount of 0.1-5 wt%, preferably 0.5-4 wt%, more preferably 0.8-3.8 wt%, c) optionally a glidant, present in an amount of 0.1-5 wt%, preferably 0.5-3 wt%, more preferably 0.8-2.5 wt%, and d) optionally a filler in an amount of 1-30 wt%, preferably 5-20 wt%, more preferably 10-15 wt% The wt% values ​​are based on the total weight of all components of the tablet.

14. A pharmaceutical composition according to any one of the preceding claims, wherein The composition is prepared by: i. wet granulating a dry mixture comprising netupitant or a salt or hydrate thereof, a filler, a binder, a disintegrant and optionally a surfactant and / or a lubricant with a solution comprising palonosetron or a salt or hydrate thereof and optionally a surfactant and / or a binder to produce granules; ii. blending the granules with a lubricant, a disintegrant and a glidant and optionally a filler, and iii. The lubricated granules are compressed to produce tablets.

15. A pharmaceutical composition according to any one of the preceding claims, wherein The tablets are uncoated.

16. A pharmaceutical composition according to any one of the preceding claims, wherein The tablets show at least 75% dissolution of netupitant after 75 minutes in a dissolution test using USP Apparatus II in 900 ml of 0.07 M phosphate buffer, pH 6.8, containing 1% SDS at a paddle speed of 100 rpm, and / or at least 75% dissolution of palonosetron after 45 minutes in a dissolution test using USP Apparatus II in 500 ml of 0.01 N HCl at a paddle speed of 75 rpm.

17. A pharmaceutical composition according to any one of the preceding claims, wherein The tablets showed a content uniformity (CU) of 85% to 115% (based on determination by HPLC analysis) and an acceptable value (AV) of less than 15 for palonosetron according to the content uniformity test of European Pharmacopoeia (Ph. Eur.) 2.9.

40.

18. Pharmaceutical composition according to any one of the preceding claims, for use in the treatment and / or prevention of nausea and / or vomiting, preferably in the treatment and / or prevention of acute or delayed nausea and vomiting associated with chemotherapy, such as highly or moderately emetogenic cancer chemotherapy, e.g. cisplatin cancer chemotherapy.

19. A method for preparing a pharmaceutical composition in the form of a tablet, the method comprising: i. wet granulating a dry mixture comprising netupitant or a salt or hydrate thereof, a filler, a binder, a disintegrant and optionally a surfactant and / or a lubricant with a solution comprising palonosetron or a salt or hydrate thereof and optionally a surfactant and / or a binder to produce granules; ii. blending the granules with a lubricant, a disintegrant and a glidant and optionally a filler, and iii. The lubricated granules are compressed to produce tablets.

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