KR20250125376A - Fixed-dose combination containing netupitant and palonosetron - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising, in a single pharmaceutical unit, a fixed-dose combination of (a) netupitant or a salt or hydrate thereof and (b) palonosetron or a salt or hydrate thereof. The present invention also relates to a process for preparing a pharmaceutical composition in tablet form, comprising the steps of (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 glidant, with a solution comprising palonosetron or a salt or hydrate thereof and optionally a surfactant and/or a binder to form granules, (ii) mixing the granules with a glidant, a disintegrant, and a fluidizing agent, and optionally a filler, and (iii) compressing the glidant-treated granules to form tablets. The present invention also relates to a pharmaceutical composition for use in the treatment and/or prevention of nausea and/or vomiting, preferably acute or delayed nausea and vomiting associated with significantly or moderately emetogenic cancer chemotherapy, such as chemotherapy with cisplatin.

Description

Fixed-dose combination containing netupitant and palonosetron

The present invention relates to the field of pharmaceutical compositions comprising netupitant or a salt or hydrate thereof and palonosetron or a salt or hydrate thereof as active ingredients.

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 process for preparing a pharmaceutical composition in tablet form, comprising the steps of (i) wet granulating a composition comprising netupitant or a salt or hydrate thereof, a filler, a binder and a disintegrant, and optionally a surfactant and/or a glidant, with a solution comprising palonosetron or a salt or hydrate thereof and optionally a surfactant and/or a binder to form granules, (ii) mixing the granules with a glidant, a disintegrant and a fluidizing agent, and optionally a filler, and (iii) compressing the glidant-treated granules to form tablets.

The present invention also relates to a pharmaceutical composition for use in the treatment and/or prevention of nausea and/or vomiting, preferably acute or delayed nausea and vomiting associated with chemotherapy, such as significantly or moderately emetogenic cancer chemotherapy, for example cisplatin cancer chemotherapy.

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]propenamide (CAS 290297-26-6), is an antinausea and antiemetic substance from the class of substances P/neurokinin 1 (NK-1) receptor antagonists. Netupitant was developed by Roche and licensed to Helsinn Healthcare in 2005.

Netupitant competitively binds to and blocks the activity of neurokinin 1 (NK-1) receptors in the central nervous system (CNS). Substance P, a neurokinin (tachykinin) neurotransmitter found in neurons in the nucleus accumbens and posterior segment of the brainstem, can be elevated in response to chemotherapy, leading to nausea and vomiting. Netupitant binds to the NK-1 receptor, thereby inhibiting the binding of Substance P to the NK-1 receptor, thereby preventing both acute and delayed nausea and vomiting during cancer chemotherapy, such as delayed nausea and vomiting that occurs after the first 24 hours after chemotherapy.

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), often used as palonosetron hydrochloride, is an anti-nausea and anti-emetic substance from the group of serotonin-3 (5-HT3) receptor antagonists. Palonosetron was discovered by Syntex Pharmaceuticals (now part of the Roche Group), which licensed it to Helsinn Healthcare in 1998.

Palonosetron acts as an antagonist at peripheral and central 5HT3 receptors, preventing serotonin binding to these receptors and thus preventing serotonin-induced nausea and vomiting, such as immediate nausea that occurs within the first 24 hours after chemotherapy administration.

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 containing netupitant 300 mg and palonosetron 0.5 mg, marketed as Akynzeo ^® by Helsinn Healthcare SA or its local marketing partners.

According to the European Public Assessment Report (EPAR), Akynzeo ^® is indicated for the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy in adults, and for the prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy. The recommended dose of Akynzeo ^® is one capsule taken orally 1 hour before the start of chemotherapy.

EP 430 190 B1 (Syntex/Roche) was the first to disclose the chemical structure of palonosetron. EP 2 099 298 A1 (Helsinn Healthcare) disclosed the amorphous and polymorphous crystalline solid states of palonosetron, including Form I and Form II of palonosetron hydrochloride.

EP 1 035 115 B1 (Roche) was the first to disclose the chemical structure of netupitant, and EP 1 776 342 B1 (Roche) disclosed a method for synthesizing netupitant. WO 16/46638 A2 (Helsinn Healthcare) disclosed three crystalline forms of netupitant, including Form I of netupitant as the only disclosed true polymorphic form and two pseudo-polymorphic forms, namely Form II of netupitant (trifluoroethanol solvate) and Form III of netupitant (formate salt).

The commercial product Akynzeo ^® is a hard capsule containing netupitant and palonosetron as separate pharmaceutical units. The hard capsule contains three netupitant tablets as individual pharmaceutical units and a soft capsule containing palonosetron as an additional separate pharmaceutical unit. Each netupitant tablet consists of 100 mg netupitant, microcrystalline cellulose, sucrose laurate, povidone K-30, croscarmellose sodium, colloidal hydrated silica, sodium stearyl fumarate, and magnesium stearate. Palonosetron soft capsules consist of (a) a capsule shell containing gelatin, glycerol, sorbitol, 1,4-sorbitan and titanium dioxide and (b) a capsule filler containing palonosetron 0.5 mg (as hydrochloride, i.e., palonosetron hydrochloride 0.56 mg), glycerol monocaprylcaproate (type I), glycerol, polyglyceryl oleate, purified water and butylated hydroxyanisole. The beneficial effects of Akynzeo ^® compared to palonosetron alone in the treatment of patients receiving chemotherapy were reported by Aapro Matti et al. (“NEPA, a fixed oral combination of netupitant and palonosetron, improves control of chemotherapy-induced nausea trial nausea and vomiting (CINV) over multiple cycles of chemotherapy: results of a randomized, double-blind, phase 3 versus oral palonosetron”, Supportive Care in Cancer, 2016).

The formulation for palonosetron soft gel capsules of the commercial product Akynzeo ^® is disclosed in EP 1 940 366 B1 (Helsinn Healthcare). EP 2 727 590 B1 discloses an Akynzeo ^® dosage form comprising an outer shell, such as a hard capsule, containing one or more netupitant units, such as tablets, and one or more palonosetron units, such as soft gel capsules.

According to the EPAR, the choice of the Akynzeo ^® dosage form, which contains individual pharmaceutical units of netupitant and palonosetron in a single hard capsule, was based on the large dose difference of the active ingredients (300 vs. 0.5 mg) and the differences in the physicochemical properties of netupitant and palonosetron, which make them difficult to co-formulate into a single pharmaceutical unit. In the solid dosage form, palonosetron showed a reduced potency and the content uniformity of netupitant and palonosetron was poor. The higher dose of netupitant 300 mg also did not have sufficient liquid solubility to be filled into soft capsules. Therefore, neither a soft capsule formulation containing both netupitant and palonosetron nor a solid dosage form could be effectively formulated.

Fixed dose combinations of netupitant and palonosetron as part of a pharmaceutical combination, preferably in the form of Akynzeo ^® , are also disclosed in US 2018/116979, WO 2020/068832 A1 and WO 2018/039159 A1.

US 2018/116979 discloses a pharmaceutical combination comprising memantine (component (a)) and an anticholinergic antiemetic (naAEA, component (b)) for the treatment of hypercholinergic disorders. The naAEA may be a fixed-dose combination of netupitant and palonosetron in the form of ^Akynzeo® . This document does not disclose any specific alternative formulations or compositions for replacing ^Akynzeo® with the netupitant/palonosetron fixed-dose combination.

WO 2020/068832 A1 discloses a pharmaceutical combination for the treatment of Parkinson's disease comprising an inhibitor (AEsI, component (a)) that inhibits the adverse effects of dopamine agonists and a dopamine agonist (component (b)). The AESI may contain a fixed-dose combination of netupitant and palonosetron. In connection with this fixed-dose combination, reference is made to US 8,951,969, which discloses Akynzeo ^® and capsules corresponding to Akynzeo ^® . This document does not disclose any specific alternative formulations or compositions to replace Akynzeo ^® for the fixed-dose combination of netupitant/palonosetron.

WO 2018/039159 A1 discloses a pharmaceutical composition for the treatment of hypercholinergic disorders, comprising an M2 receptor antagonist (component (a)) and an anticholinergic antiemetic (naAEA, component (b)). The naAEA may be an oral fixed-dose combination of netupitant and palonosetron. However, the specific formulation and composition for the netupitant/palonosetron combination are not disclosed in this document.

The formulation and production of dosage forms containing different types of pharmaceutical units and dosage forms into a single dosage form, such as the commercial product Akynzeo ^® , is typically a complex and time-consuming process, as the different types of pharmaceutical units must be manufactured separately in separate manufacturing processes and then combined into a single dosage form in a further manufacturing step.

The formulation and production of softgel capsules, such as those containing palonosetron in the commercial product Akynzeo ^® , is typically time-consuming and/or requires a large number of excipients and often specialized equipment. The manufacturing process for softgel capsules typically consists of several main steps, including preparation of the fill mixture (dissolving palonosetron and excipients in the fill solution), preparation of the gelatin material, encapsulation and lubrication into soft capsules, drying, sizing, washing, and bulk packaging. The manufacturing process for netupitant tablets in the commercial product Akynzeo ^® consists of several main steps, including mixing netupitant and excipients, high-shear wet granulation, drying, milling, mixing with additional excipients, compression, and bulk packaging. Therefore, the overall manufacturing process for Akynzeo ^® hard capsules filled with netupitant tablets and palonosetron soft capsules is a relatively complex and time-consuming manufacturing process.

Additionally, the commercial product Akynzeo ^® is a large capsule measuring approximately 22 mm in length, which may be difficult to swallow and result in poor patient compliance.

Difficulty swallowing tablets and capsules can be problematic for many individuals, leading to non-compliance with treatment regimens and a variety of adverse events. It is estimated that more than 16 million people in the United States have difficulty swallowing, also known as dysphagia. For these individuals, swallowing tablets or capsules can be particularly challenging. Surveys of adults with difficulty swallowing tablets and capsules suggest that this problem may affect up to 40% of the American population, far beyond the clinically recognized dysphagia population. Individuals who have difficulty swallowing tablets and capsules often cite their size as the primary reason for their difficulty.

The size and shape of tablets and capsules affect how the product passes through the pharynx and esophagus, and can directly impact a patient's ability to swallow certain medications. Larger tablets and capsules have been shown to take longer to pass through the esophagus. This can lead to disintegration of the medication in the esophagus and/or damage to the esophagus, potentially leading to pain and localized esophagitis, as well as serious side effects such as ulcers, strictures, and perforations. Other adverse events, such as pain, vomiting, choking, and aspiration, are associated with dysphagia during oropharyngeal swallowing and occur more frequently with larger tablets and capsules.

Various other factors can also affect a patient's ability to swallow tablets or capsules. For example, age can be a factor. Children, adolescents, and 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.

Patient compliance with medication regimens can be influenced by the size and shape of tablets or capsules. Human studies have suggested that oval-shaped or capsule-shaped tablets are easier to swallow than round tablets of the same weight. The maximum dimension of a tablet or capsule should not exceed 22 mm. Generally, a maximum dimension of 17 mm is recommended for tablets or capsules.

The commercially available product, Akynzeo® ^, is a large capsule measuring 7.6 mm thick and approximately 22 mm long, the maximum dimensions permitted for oral medications. Given its approved indication for preventing nausea and vomiting associated with cancer chemotherapy and the fact that cancer patients often take multiple medications daily, patients may typically have difficulty swallowing medications, leading to poor compliance, which is further reduced by the large capsule size.

Although combination dosage forms of netupitant and palonosetron are available, these formulations involve complex, costly, and time-consuming manufacturing processes involving multiple steps. Furthermore, these oral dosage forms are bulky and difficult to swallow, which impacts patient compliance. Therefore, there is a need for improved and more efficient means of formulating combination pharmaceutical compositions of netupitant and palonosetron that address the shortcomings of the prior art and employ simple, reliable compositions and methods for easily preparing cost-effective, stable dosage forms with desirable properties for medical applications.

In light of the prior art, the technical problem underlying the present invention is to provide an improved or alternative means for a pharmaceutical composition comprising a fixed dose combination of netupitant or a salt or hydrate thereof and palonosetron or a salt or hydrate thereof.

A further object of the present invention is to provide improved or alternative means for pharmaceutical compositions comprising a fixed dose combination of netupitant or a salt or hydrate thereof and palonosetron or a salt or hydrate thereof, which exhibits comparable or improved solubility and/or oral availability compared to available dosage forms, such as hard capsules containing netupitant tablets and soft capsules containing palonosetron.

A further object of the present invention is to provide an improved or alternative means for preparing a pharmaceutical composition comprising a fixed dose combination of netupitant or a salt or hydrate thereof and palonosetron or a salt or hydrate thereof, which is technically reliable, simple and/or cost-effective in its manufacture.

A further object of the present invention is to provide an improved or alternative means for producing a fixed-dose combination pharmaceutical composition for oral use comprising netupitant or a salt or hydrate thereof and palonosetron or a salt or hydrate thereof, which has better swallowability and better patient compliance compared to available dosage forms. In providing a solution to this problem, the present invention seeks to avoid the shortcomings of the prior art.

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

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.

Surprisingly, the composition of the present invention comprises netupitant and palonosetron in a single pharmaceutical unit, and exhibits excellent content uniformity and stability. To the best of the inventors' knowledge, the composition of the present invention is the first effective pharmaceutical composition to incorporate netupitant and palonosetron as a mixture, i.e., in a single pharmaceutical unit. In other words, the composition represents an unexpected technological advancement in the combination formulation of these two APIs.

To date, prior art has taught that, due to the significant differences in dosage, physicochemical properties, and content uniformity between the two active pharmaceutical ingredients (APIs), an effective combination formulation of netupitant and palonosetron must be prepared by manufacturing individual pharmaceutical units for each API and then co-filling these into hard capsule shells. This results in a time-consuming and cost-intensive manufacturing process involving multiple steps: manufacturing individual pharmaceutical units for each API and then combining them.

The composition of the present invention advantageously allows netupitant and palonosetron to be formulated into a single pharmaceutical unit, thereby enabling a simpler, less complex, more cost-effective, and more technically reliable manufacturing process compared to prior art.

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

Surprisingly, the composition of the present invention, comprising netupitant and palonosetron in a single pharmaceutical unit, can be formulated into a solid dosage form, such as a tablet, in contrast to prior art formulations. In a preferred embodiment, the tablet of the present invention provides a simple and unexpectedly effective composition, considering the previously disclosed problems with the two APIs.

The prior art teaches that it has not been possible to formulate two APIs into a single solid dosage form, such as a tablet, because of the significant difference in dosage and, in particular, the difference in physicochemical properties, which results in a reduced efficacy of palonosetron and poor content uniformity, and also because it is not possible to obtain a solvent suitable for dissolving both APIs, and therefore it is not possible to formulate, for example, a soft capsule containing both APIs in a capsule filler.

The composition of the present invention in tablet form comprising netupitant and palonosetron as a fixed-dose combination unexpectedly has high content uniformity, high stability, and similar or improved solubility compared to the reference formulation Akynzeo ^® . Furthermore, the composition of the present invention exhibits low variability with respect to dissolution, which is advantageous with respect to low variability and thus advantageous with respect to absorption and bioavailability of the active ingredients. In contrast, the reference formulation Akynzeo ^® exhibits relatively high dissolution variability, which can be influenced by the dissolution of the dosage form due to the formulation comprising the active ingredients as individual dosage forms and their repackaging within a hard capsule shell. Therefore, a tablet formulation comprising both APIs as a fixed-dose combination offers the advantage of a stable formulation with desirable properties for medical use, such as improved dissolution characteristics, while at the same time being easy, technically reliable, and cost-effective to manufacture. This combination of improved properties compared to the prior art would not have been anticipated by one skilled in the art in light of the teachings of the prior art.

In an embodiment, the pharmaceutical composition in tablet form has a size in which the longest dimension does not exceed 17.5 mm. In an embodiment, the pharmaceutical composition in tablet form has a size in which the longest dimension does not exceed 17 mm, preferably does not exceed 15 mm, more preferably does not exceed 14 mm.

In an embodiment, the pharmaceutical composition in tablet form has a size in which the longest dimension is no greater than 17.5 mm. In an embodiment, the pharmaceutical composition in tablet form has a size in which the longest dimension is no greater than 17 mm, preferably no greater than 15 mm, more preferably no greater than 14 mm.

In an embodiment, the tablet has an oval or capsule shape.

The composition of the present invention advantageously allows netupitant and palonosetron to be formulated into tablets of smaller size than previously available dosage forms. Therefore, the tablets of the present invention offer the advantage of easier swallowing when administered orally, i.e., improved patient compliance.

The commercially available product ^Akynzeo® is a large capsule measuring approximately 22 mm in length. Since the size and shape of an oral dosage form can directly impact swallowability and its transit through the pharynx and esophagus, patient compliance with ^Akynzeo® , given its indication for preventing nausea and vomiting associated with cancer chemotherapy, may be substantially reduced. Prior art formulations require netupitant and palonosetron to be formulated as individual pharmaceutical dosage forms, which cannot be effectively packaged as a single dosage form, requiring, for example, a large, hard capsule shell. In contrast, the present formulation effectively formulates and compresses the active ingredients into a single pharmaceutical unit in tablet form, which is substantially smaller, lighter, and easier to swallow compared to prior art formulations. Therefore, providing the present composition in a smaller tablet form offers an unexpected technical advantage over prior art formulations, making dosing easier and more reliable, thereby improving 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 granular phase.

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

The mixing and combining of the APIs of the present invention into the same granular phase of a single composition is unexpected compared to the prior art. Surprisingly, the two APIs can be combined and prepared by mixing and granulating, for example, a dry mixture containing netupitant with a liquid containing palonosetron, thereby maintaining the two APIs in a single (preferably intragranular) phase. In an embodiment, the granules are treated with a lubricant and subsequently compressed to obtain a simple and effective composition. The achievement of acceptable content uniformity and solubility of the two APIs in such a composition was unexpected in the prior art.

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.

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 croscarmellose sodium, sodium starch glycolate, crospovidone and/or pregelatinized starch, and the glidant is magnesium stearate and/or sodium stearyl fumarate.

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

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.

In one embodiment of the present invention, the lubricant is magnesium stearate and/or sodium stearyl fumarate, the disintegrant is croscarmellose sodium, sodium starch glycolate, crospovidone and/or pregelatinized starch, the fluidizing agent is colloidal silicon dioxide, and the filler is microcrystalline cellulose and/or mannitol.

In one embodiment of the present invention, the pharmaceutical composition does not comprise titanium dioxide (TiO ₂ ).

Advantageously, unlike the commercial product Akynzeo ^® , which uses titanium dioxide as an opacifier and colorant in oral dosage forms such as tablets, granules, hard capsules, and soft gel capsules, the compositions of the present invention do not use titanium dioxide. Recent safety assessments have raised concerns about genotoxicity of titanium dioxide. Therefore, titanium dioxide is no longer considered safe as a food additive according to the EMA and should be avoided or replaced with alternative excipients in pharmaceutical compositions. Thus, the compositions of the present invention represent a technological advance over prior art in that they avoid the use of titanium dioxide in combination formulations comprising netupitant and palonosetron.

In one embodiment of the present invention, the pharmaceutical composition does not contain any animal or animal-derived products. In one embodiment of the present invention, the pharmaceutical composition does not contain any animal-derived excipients. In one embodiment of the present invention, the pharmaceutical composition is vegan.

Advantageously, the compositions of the present invention are free of animal-derived excipients. In contrast, the commercially available product ^Akynzeo® contains several animal-derived excipients, including bovine-derived gelatin in the hard capsule shell and shellac in the printing ink. Thus, the compositions of the present invention represent a technological advance over prior art in that they omit the use of animal-derived excipients. Therefore, the compositions of the present invention are also applicable to the growing global vegan population, which avoids the use of animal-derived products. Furthermore, the vegan formulations can be used by patients who follow a halal or kosher diet and/or who do not consume certain animal-derived products for religious reasons. Therefore, these formulations may be advantageously applicable to a larger patient population compared to prior art formulations.

In one embodiment of the present invention, the pharmaceutical composition comprises an intragranular phase and an extragranular phase, and the disintegrant is present in both granular phases in an intragranular phase:extragranular phase weight ratio of 5:1 to 1:5, preferably 2:1 to 1:2, more preferably 1:1, and the disintegrant is preferably croscarmellose sodium, sodium starch glycolate, crospovidone and/or pregelatinized starch. In one embodiment, the disintegrant is present in both granular phases, preferably in an intragranular phase:extragranular phase weight ratio of 5:1 to 1:5, for example 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.

Surprisingly, the composition of the present invention exhibits advantageous dissolution properties compared to ^Akynzeo® formulations according to the prior art. The presence of a disintegrant in both granular phases, in combination with the aforementioned excipients, surprisingly facilitates dissolution, particularly of netupitant, an AIP with typically low solubility. Thus, the disintegrant present in the extragranular phase first disintegrates the tablet into granules, thereby advantageously dissolving and dissolving the active ingredients netupitant and palonosetron.

In one embodiment of the present invention, the pharmaceutical composition does not comprise an antioxidant.

In one embodiment of the present invention, the pharmaceutical composition comprises (i) netupitant or a salt or hydrate thereof, present in a content 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 a content of 0.05-0.5 wt%, preferably 0.08-0.3 wt%, more preferably 0.1-0.2 wt%, a filler, present in a content of 2-40 wt%, preferably 5-35 wt%, more preferably 6-32 wt%, a binder, present in a content of 0.1-10 wt%, preferably 0.5-9 wt%, more preferably 0.8-8 wt%, a binder, present in a content of 0.1-5 wt%, preferably 0.5-4 wt%, more preferably 0.8-3.8 An intragranular combination comprising (i) a disintegrant present in a content of 0.1-5 wt%, preferably 0.5-4 wt%, more preferably 0.8-3.5 wt%, a surfactant optionally present in a content of 0.1-5 wt%, preferably 0.5-3 wt%, more preferably 0.8-1.5 wt%, and (ii) a glidant present in a content 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%, a disintegrant optionally present in a content of 0.1-5 wt%, preferably 0.5-4 wt%, more preferably 0.8-3.8 wt%, and (iii) a surfactant optionally present in a content of 0.1-5 wt%, preferably 0.5-3 wt%, more preferably 0.8-2.6 wt%, even more preferably 0.8-2.6 wt%, and An extragranular component comprising a fluidizing agent present in an amount of 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.

All values provided above, e.g. specific preferred values for each component, may have a deviation of +/- 2 wt%, +/- 1 wt% or +/- 0.5 wt%.

The embodiments below are also considered to encompass additional embodiments utilizing the components in the indicated amounts. These embodiments are not limited by the total weight of the composition, but in some embodiments are limited by the wt% value of each component in the tablet and/or the presence of each component, and are not limited to absolute values. The preferred wt% weight ranges may be adopted for any given characteristic as a defining characteristic of the composition, but do not inherently limit the specific weights or combination possibilities with other components in the formulation employed in each example.

Embodiment E1 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 88.09 19.58 2-40 3 Povidone Ph. Eur. binder 21:00 4.67 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E2 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 88.09 19.58 2-40 3 Povidone Ph. Eur. binder 21:00 4.67 0.1-10 4 Poloxamer 188 Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E3 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 103.09 22.91 2-20 3 Povidone Ph. Eur. binder 21:00 4.67 0.1-10 4 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Implementation Example E4 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 73.09 16.24 2-20 3 Povidone Ph. Eur. binder 31.50 7.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 6.75 1.50 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 6.75 1.50 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Implementation Example E5 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 73.09 16.24 2-40 3 Povidone Ph. Eur. binder 22.50 5.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.50 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.50 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E6 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 73.09 16.24 2-20 3 Povidone Ph. Eur. binder 13.50 3.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 15.75 3.50 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 15.75 3.50 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E7 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 91.09 20.24 2-40 3 Povidone Ph. Eur. binder 13.50 3.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 6.75 1.50 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 6.75 1.50 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Implementation Example E8 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 55.09 12.24 2-40 3 Povidone Ph. Eur. binder 31.50 7.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 15.75 3.50 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 0.05-5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 15.75 3.50 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E9 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 60.00 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 64.72 12.94 2-40 3 Mannitol Ph. Eur. filler 64.72 12.94 2-40 4 Povidone Ph. Eur. binder 20.00 4.00 0.1-10 5 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.00 0.1-5 6 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.11 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 10.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 5.00 1.00 0.1-5 Tablet weight (mg): 500.00 100.00

Implementation Example E10 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 60.00 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 32.36 6.74 2-40 3 Mannitol Ph. Eur. filler 97.08 19.42 2-40 4 Povidone Ph. Eur. binder 20.00 4.00 0.1-10 5 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.00 0.1-5 6 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.11 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 10.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 5.00 1.00 0.1-5 Tablet weight (mg): 500.00 100.00

Embodiment E11 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 60.00 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 97.08 19.42 2-40 3 Mannitol Ph. Eur. filler 32.36 6.47 2-40 4 Povidone Ph. Eur. binder 20.00 4.00 0.1-10 5 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.00 0.1-5 6 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.11 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 10.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 5.00 1.00 0.1-5 Tablet weight (mg): 500.00 100.00

Embodiment E12 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 60.00 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 77.22 15.44 2-40 3 Mannitol Ph. Eur. filler 77.22 15.44 2-40 4 Povidone Ph. Eur. binder 5.00 1.00 0.1-10 5 Sodium Lauryl Sulfate Ph. Eur. surfactant 5.00 1.00 0.1-5 6 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.11 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 10.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 5.00 1.00 0.1-5 Tablet weight (mg): 500.00 100.00

Embodiment E13 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 Polysorbate 20 Ph. Eur. surfactant 15.00 3.33 0.1-5 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Implementation Example E14 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 Polysorbate 80 Ph. Eur. surfactant 15.00 3.33 0.1-5 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E15 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 Sorbitan monolaurate Ph. Eur. surfactant 15.00 3.33 0.1-5 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Implementation Example E16 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 Sorbitan monooleate Ph. Eur. surfactant 15.00 3.33 0.1-5 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Implementation Example E17 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 18:00 4.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Implementation Example E18 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 18:00 4.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 2 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Implementation Example E19 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Sodium Starch Glycolate Ph. Eur. disintegrant 9.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Sodium Starch Glycolate Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E20 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Crospovidone Ph. Eur. disintegrant 9.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Crospovidone Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E21 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Pregelatinized starch Ph. Eur. disintegrant 9.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Pregelatinized starch Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E22 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Povidone Ph. Eur. binder 9.00 2.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 Povidone Ph. Eur. binder 9.00 2.00 0.1-10 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E23 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Copovidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.0-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E24 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 3 Corn starch Ph. Eur. binder 18:00 4.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E25 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Top-A (Mixed): 1 Palonosetron hydrochloride In-house API 0.56 0.12 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 80.44 17.88 2-40 Phase B (Mixed & Compressed): 1 Netupitant In-house API 300.00 67.67 0.05-0.5 2 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 3 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 4 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 5 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Sang-C (Active): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E26 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Top-A (Mixed): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 Cellulose, microcrystalline Ph. Eur. filler 84.94 18.88 2-40 Phase B (Mixed & Co-Crushed): 1 Netupitant In-house API 300.00 67.67 50-75 2 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 3 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 4 Croscarmellose Sodium Ph. Eur. disintegrant 18:00 4.00 0.1-5 5 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 Phase C (Mixed): 1 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E27 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 80.44 17.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E28 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 80.44 17.88 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium Stearate Ph. Eur lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E29 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 50-75 2 Mannitol Ph. Eur. filler 30.00 6.67 2-40 3 Povidone Ph. Eur. binder 18:00 4.00 0.1-10 4 Croscarmellose Sodium Ph. Eur. disintegrant 14:00 3.11 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 Polysorbate 80 Ph. Eur. surfactant 15.00 3.33 0.1-5 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Cellulose, microcrystalline Ph. Eur. filler 49.94 11.10 1-30 2 Croscarmellose Sodium Ph. Eur. disintegrant 14:00 3.11 0.1-5 3 Colloidal silicon dioxide Ph. Eur. Fluidizer 4.00 0.89 0.1-5 4 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E30 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 19.89 4.42 2-40 4 Mannitol Ph. Eur. filler 68.20 15.16 2-40 3 Povidone Ph. Eur. binder 13.50 3.00 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 4.5 1.00 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.50 0.1-5 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.00 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.50 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.00 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E31 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.96 66.22 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 44.51 9.79 2-40 4 Mannitol Ph. Eur. filler 45.47 10.00 2-40 3 Povidone Ph. Eur. binder 13.50 2.97 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 4.5 0.99 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.48 0.1-5 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 0.99 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.48 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 1.98 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 9.00 1.98 0.1-5 Tablet weight (mg): 454.50 100.00

Embodiment E32 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 300.96 66.22 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 67.24 14.79 2-40 4 Mannitol Ph. Eur. filler 22.74 5.00 2-40 3 Povidone Ph. Eur. binder 13.50 2.97 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 4.5 0.99 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.48 0.1-5 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 0.99 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.48 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 1.98 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 9.00 1.98 0.1-5 Tablet weight (mg): 454.50 100.00

Embodiment E33 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 302.11 69.21 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 16.120 3.69 2-40 4 Mannitol Ph. Eur. filler 54.705 12.53 2-40 3 Povidone Ph. Eur. binder 13.50 3.09 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 4.5 1.03 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.58 0.1-5 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.03 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.13 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.58 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.06 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 9.00 2.06 0.1-5 Tablet weight (mg): 450.00 100.00

Embodiment E34 - Netupitant/palonosetron 300 mg/0.5 mg tablets:

S. No. ingredient function mg/tablet Refined weight % Preferred weight % range Phase A (granulation): 1 Netupitant In-house API 301.75 69.21 50-75 2 Cellulose, microcrystalline Ph. Eur. filler 34.47 7.91 2-40 4 Mannitol Ph. Eur. filler 36.22 8.31 2-40 3 Povidone Ph. Eur. binder 13.50 3.10 0.1-10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 4.5 1.03 0.1-5 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.58 0.1-5 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.03 0.1-5 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.13 0.05-0.5 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.58 0.1-5 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.06 0.1-5 3 Magnesium stearate Ph. Eur. lubricant 9.00 2.06 0.1-5 Tablet weight (mg): 436.50 100.00

In one embodiment of the present invention, the tablet is uncoated.

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

In one embodiment of the present invention, the tablet has a content uniformity (CU) of palonosetron of 85% to 115% (based on HPLC analysis) according to the content uniformity test of European Pharmacopoeia (Ph. Eur.) 2.9.40 and an acceptance value (AV) of less than 15.

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 for use in the treatment and/or prevention of acute or delayed nausea and vomiting associated with chemotherapy, for example, with significantly or moderately emetogenic cancer chemotherapy, for example, with cisplatin cancer chemotherapy.

Accordingly, the present invention relates to a method for treating and/or preventing nausea and/or vomiting, for example, a method for treating a subject experiencing nausea and/or vomiting, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein.

In a further embodiment, the nausea and/or vomiting is selected from the list of acute or delayed nausea and vomiting associated with chemotherapy, e.g., significantly or moderately emetogenic cancer chemotherapy, e.g., cisplatin cancer chemotherapy.

In another aspect, the present invention relates to a process for preparing a pharmaceutical composition in tablet form, comprising the steps of (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 glidant, with a solution comprising palonosetron or a salt or hydrate thereof and optionally a surfactant and/or a binder to prepare granules, (ii) mixing the granules with a glidant, a disintegrant, and a fluidizing agent, and optionally a filler, and (iii) compressing the glidant-treated granules to prepare tablets.

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

The simple and cost-effective manufacturing process for preparing tablets containing both netupitant and palonosetron of the present invention relates to a single manufacturing process comprising directly granulating a mixture of netupitant and excipients with a palonosetron solution to form granules, which are subsequently compressed into tablets. In contrast, the prior art formulation Akynzeo ^® requires that netupitant and palonosetron be manufactured into separate types of pharmaceutical units (netupitant tablets and palonosetron soft capsules) in separate manufacturing processes, which is complex and time-consuming. These pharmaceutical units must then be combined into a single dosage form in an additional manufacturing step. The present invention therefore allows for a simpler, less complex and more cost-effective process for preparing tablets containing both netupitant and palonosetron in a single pharmaceutical unit, which is equivalent and improved in terms of stability, content uniformity and dissolution properties compared to the prior art formulations.

The aforementioned features of the method for preparing a pharmaceutical composition achieve structural and functional results in the tablets and dispersions of the present invention, so that the tablets and dispersions may in some embodiments be described by or derived from the features of the method for preparing the pharmaceutical composition, or vice versa.

Detailed Description of the Invention

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

The chemical structure of netupitant is as follows:

Netupitant and its salts or hydrates are selective antagonists of neurokinin 1 (NK-1) receptors. Activation of NK-1 receptors by substance P, which are widely distributed throughout the central and peripheral nervous systems (CNS and PNS), such as the gastrointestinal tract (GIT) and the posterior locus and nucleus accumbens, is associated with nausea and vomiting, particularly delayed nausea and vomiting. Netupitant prevents acute and delayed nausea and vomiting, for example, during chemotherapy for cancer, by inhibiting and/or reducing the binding of substance P to the receptor, i.e., by inhibiting neuronal activation.

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 substances belonging to the group of serotonin-3 (5-HT3) receptor antagonists. Palonosetron hydrochloride is a non-hygroscopic white crystalline powder, soluble in water, slightly soluble in polar organic solvents and insoluble in most non-polar organic solvents.

The chemical structure of palonosetron is as follows:

Palonosetron and its salts or hydrates are 5-HT3 receptor antagonists. The release of serotonin, also referred to as "5-HT," from enterochromaffin cells into the small intestine, such as during chemotherapy, is associated with nausea and vomiting due to activation of 5-HT3 receptors on vagal afferents. Vagal afferent activation also triggers the release of serotonin in the posterior lobe, which may further promote vomiting. 5-HT3 receptor antagonists, also called "setrons," such as palonosetron or its salts or hydrates, inhibit this action by antagonizing its binding to peripheral and central 5-HT3 receptors, thereby reducing or preventing serotonin from binding to 5-HT3 receptors.

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 netupitant 300 mg and palonosetron 0.5 mg. It is marketed as Akynzeo ^® by Helsinn Healthcare or its regional marketing partners.

Akynzeo ^® is indicated for the prevention of acute and delayed nausea and vomiting associated with significantly emetogenic cisplatin-based cancer chemotherapy and for the prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

Nausea and vomiting are frequent, usually non-specific, accompaniments to various diseases, including viruses (e.g., rotavirus, adenovirus, coronavirus, and norovirus), bacteria (e.g., Salmonella, Campylobacter, Shigella, Yersinia, Clostridium difficile, and Vibrio cholerae), protozoa (e.g., amoebae, giardia), stomach diseases, gallbladder diseases, chronic pancreatitis, ureaemia, hepatic coma, vestibular vertigo, Meniere's disease, increased intracranial pressure (e.g., due to previous traumatic brain injury, intracerebral hemorrhage, meningitis, and brain cancer), migraine attacks, psychovegetative reactions to visual, olfactory, acoustic, and auditory stimuli, kinetosis, hyperemesis gravidarium, depression, anxiety, Various factors may be considered, including anorexia, bulimia, excessive alcohol consumption, and emetogenic drugs or treatments (e.g., chemotherapy, digitalis glycosides, opioids, apomorphine, and radiation therapy). Physiologically, nausea and vomiting, also called "emesis," are related to afferent impulses from the digestive tract to the vomiting center in the medulla oblongata, either due to stimulation of chemoreceptors in the posterior medullary area or due to vestibular stimulation. Receptors involved in nausea and vomiting include D2-, 5-HT3, neurokinin-1 (NK-1), H1 receptors, and m-cholinoceptors.

When administered chemotherapy, also known as "cancer chemotherapy,""chemotherapeuticagent,""chemotherapy," or radiotherapy, nausea and vomiting may occur immediately (acute nausea and/or vomiting) or delayed (delayed nausea and/or vomiting) after the first 24 hours. Chemotherapeutic agents can be classified according to their emetogenic potential. When chemotherapeutic agents are combined, the emetogenic potential of the regimen is assessed based on the most emetogenic chemotherapeutic agent. Significantly emetogenic chemotherapeutic agents induce vomiting in >90% of patients and include, but are not limited to, cisplatin, cyclophosphamide ≥1500 mg/m ² , streptozotocin, carmustine, dactinomycin, mechlorethamine, streptozotocin, and dacarbazine. Moderately emetogenic chemotherapeutic agents induce vomiting in 30-90% 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 chemotherapeutic agents induce vomiting in 10-30% 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 chemotherapeutic agents, also called minimally emetogenic chemotherapeutic agents, induce vomiting in <10% of patients and include, but are not limited to, vinca-alkaloids and bleomycin.

Treatment and/or prevention of nausea and/or vomiting, for example acute and/or delayed nausea and vomiting associated with chemotherapy, for example significantly and/or moderately emetogenic cancer chemotherapy, represents a preferred embodiment for the medical use of the present invention.

"Administration" or "treatment" refers to bringing a pharmaceutical, therapeutic, or diagnostic substance, compound, or composition into contact with an animal, human, subject, cell, tissue, organ, or biological fluid. "Administration" and "treatment" may also refer to, for example, therapeutic, placebo, pharmacokinetic, diagnostic, research, and experimental methods. "Treatment" refers to therapeutic treatment, prophylactic or preventative measures, research, and diagnostic applications when applied to a human, veterinary, or research subject.

The present invention encompasses administering an effective amount of a chemical substance described herein to a subject or patient in need thereof. An "effective amount" or "therapeutically effective amount" means an amount sufficient, when administered to a subject or patient, to produce a significant biological response, such as an improvement in the symptoms or signs of a disorder or pathological condition. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated and the patient's overall health and age. The effective amount may be the maximum dose or administration protocol that avoids significant side effects or toxic effects. An "effective amount" also relates to an amount of a substance or pharmaceutical composition thereof sufficient to permit or promote a significant biological response, such as an improvement in the symptoms or signs of a disorder, condition, or pathological condition.

The term "active ingredient" or "API" herein refers to the pharmaceutically active molecules netupitant and/or palonosetron, as well as pharmaceutically acceptable and/or therapeutically active salts thereof (e.g., palonosetron hydrochloride). The term additionally refers to pharmaceutically acceptable and therapeutically active hydrates, esters, amides, metabolites, enantiomers, polymorphs, analogs, etc., which induce a desired pharmacological or physiological effect or which, when converted to the pharmaceutically active molecule in an organism, induce a desired pharmacological or physiological effect. Terms such as "active substance," "active pharmaceutical ingredient," and "drug substance" may be used synonymously with "active ingredient." The term "pharmaceutically active molecule" herein refers to a substance that induces a desired pharmacological or physiological effect in an organism and/or subject. Terms such as “active drug”, “active molecule”, “therapeutically active molecule”, and “therapeutically active drug” may be used synonymously with “pharmaceutically active molecule”.

The present invention further relates to salts of netupitant and/or palonosetron. The term "salt" refers to salts prepared by conventional means encompassing basic salts of inorganic and organic acids, such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, also called esylate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, Examples include, but are not limited to, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, saccharate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. For therapeutic use, salts of the compounds are those in which the counter ion 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.

The term "excipient" refers to non-pharmacologically active ingredients in pharmaceutical products, such as fillers, lubricants, binders, disintegrants, fluidizing agents, flavoring agents, sweeteners, coloring agents, film formers, gelling agents, acid regulators, preservatives, absorption enhancers, and stabilizers. Excipients usable in the manufacture of pharmaceutical compositions are generally safe, non-toxic, and acceptable for both veterinary and human pharmaceutical use. References to an excipient include both a single excipient and two or more excipients.

Excipients are described herein in some embodiments as "wt%", or "weight percentage" or "weight %." The %wt figure relates to the weight % of the substance present in the pharmaceutical composition in tablet form.

According to the present invention, fillers can be used as bulking agents in solid dosage forms such as tablets and granules. Fillers used in tablets include, but are not limited to, sugars and sugar alcohols such as lactose, saccharose, 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.; and inorganic fillers such as calcium phosphate, calcium hydrogen phosphate, calcium carbonate, and mixtures thereof. Preferred fillers according to the present invention are microcrystalline cellulose (MCC) and/or mannitol.

Microcrystalline cellulose (MCC) is obtained from cellulose by heat treating it with a mineral acid and then mechanically comminuting the cellulose aggregates. The acid treatment causes limited hydrolysis, reducing the degree of polymerization (DP) to approximately 200-300 and increasing the degree of crystallinity. Subsequently, spray drying of the dispersant yields a powder of aggregated cellulose crystals suitable for direct tablet compression. Due to its high plasticity, microcrystalline cellulose contributes to tablet hardness and reduces tablet friability. Furthermore, tablet compression can be performed at lower compression pressures, reducing the tablet density and facilitating rapid disintegration and dissolution.

Mannitol (CAS No. 69-65-8) is a dihydric sugar alcohol structurally derived from mannose, occurring naturally in plants, algae, and lichens. In the pharmaceutical industry, mannitol is used as a filler, sweetener, and binder. Because mannitol can be easily compressed and bound, it is commonly used as a filler to produce small, stable tablets. In the context of the present invention, mannitol is defined as a filler.

Fluidizing agents improve the flow characteristics of powder mixtures by reducing interparticle friction. Therefore, they improve dosing accuracy. Highly dispersed silicon dioxide is particularly useful as a fluidizing agent.

Silicon dioxide is an oxide of silicon. It is a naturally occurring material that occurs crystalline in quartz, granite, and sand, and is used in the manufacture of glass. Various grades of silicon dioxide are widely used as excipients in the pharmaceutical industry. Highly dispersed silicon dioxide, also known as "colloidal silicon dioxide," is used as a fluidizing agent. Colloidal or highly dispersed silicon dioxide is produced through flame hydrolysis of SiCl ₄ , resulting in submicroscopic, amorphous spheres with a diameter of approximately 7-16 nm and a very large surface area of approximately 200 m ² /g. A small addition of approximately 0.5% is typically sufficient to significantly improve the flow properties of the powder. The preferred fluidizing agent in the present invention is colloidal silicon dioxide.

Disintegrants are excipients used in tablets that cause the tablet to disintegrate, dissolve, and release its active ingredient upon contact with moisture. Disintegrants can be categorized into substances that increase capillary action, absorb moisture, and swell, compounds that release gas and release upon exposure to moisture, and substances that increase the wettability of tablets (hydrophilizing agents).

Substances that increase capillary inertia include soybean polysaccharides, alginic acid, cross-linked alginic acid, calcium alginate, sodium alginate, starches such as corn starch, pretreated starches such as pregelatinized starch, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (also called croscarmellose sodium), cross-linked calcium carboxymethyl cellulose (also called carmellose calcium), cross-linked sodium carboxymethyl starch (also called sodium starch glycolate), low-substituted hydroxypropyl cellulose (L-HPC) and cross-linked polyvinylpyrrolidone (also called crospovidone). An important part of the function of this group is the swelling pressure, porosity and wettability exerted on the tablet, which affect the water permeability of the tablet, which is a prerequisite for the disintegration process. These disintegrants are very effective if they have high swelling properties and high swelling pressure, form a pore system in the tablet, and have sufficient wettability.

Highly effective disintegrants, which are highly effective at much lower concentrations than other disintegrants and have higher disintegration efficiency and mechanical strength, are called superdisintegrants. Superdisintegrants include cross-linked sodium carboxymethyl cellulose (also called "croscarmellose sodium"), cross-linked calcium carboxymethyl cellulose (also called "carmellose calcium"), cross-linked sodium carboxymethyl starch (also called "sodium starch glycolate"), and cross-linked polyvinylpyrrolidone (also called "crospovidone"). These water-insoluble substances possess high swelling capacity as well as high capillary activity, ensuring spontaneous and complete disintegration without mucus formation.

Compounds that release gas upon exposure to moisture include sodium hydrogen carbonate and combinations of hydrogen carbonate and citric or tartaric acid. Tablets containing these disintegrants rapidly disintegrate due to the release of carbon dioxide during the acid reaction. These disintegrants are commonly used in oral tablets or effervescent tablets.

Hydrophilizing agents include sodium lauryl sulfate, polysorbates, highly dispersed silicon dioxide, and microcrystalline cellulose. Representative materials in this group are not technically considered disintegrants themselves. Rather, they facilitate the optimal functioning of the disintegrant. Manufacturing lipophilic substances into tablets often presents significant challenges, as these tablets have low wettability, resulting in the disintegrant not working effectively or only having a very delayed effect. The addition of surface-active substances/hydrophilizing agents to hydrophilize the tablet ensures water penetration into the tablet, allowing the added disintegrant to act.

In embodiments of the present invention, preferred disintegrants are super-disintegrants, preferably croscarmellose sodium, sodium starch glycolate, crospovidone and/or pregelatinized starch.

Crospovidone (also known as cross-linked polyvinyl N-pyrrolidone, polyvinyl polypyrrolidone, or PVPP) is a free-flowing, inert, and insoluble white to pale yellow powder. It has excellent swelling properties, along with hygroscopic or water-attracting properties, making it useful as a disintegrant in pharmaceutical dosage forms. Crospovidone is not absorbed orally. Oral use of crospovidone is not usually associated with toxicity when used as a pharmaceutical excipient.

Sodium starch glycolate is the sodium salt of starch carboxymethyl ether. Starch glycolate is derived from rice, potatoes, and/or corn. Sodium starch glycolate rapidly absorbs water, causing swelling and rapid tablet disintegration.

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

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

Pregelatinized starch (PGS) is generally considered a filler (diluent), but it also has some disintegrant-like properties, and can be considered a "filler-disintegrant." PGS may also have binder-like properties. Therefore, PGS is a multifunctional excipient. PGS is starch that has been chemically and/or mechanically treated to destroy some or all of the starch granules. This typically imparts flowability and direct compressibility to the starch (Handbook of Pharmaceutical Excipients (Ed: Rowe)). Some pregelatinized starches are commercially available. In some embodiments, the pregelatinized starch contains 5% free amylose, 15% free amylopectin, and 80% unmodified starch. Pregelatinized starch is typically obtained from corn, potato, or rice starch. Pregelatinized starch can be employed in granular or tablet formulations, and serves various functions as a filler, disintegrant, and/or binder. In the context of the present invention, PGS is defined as a disintegrant.

Glidants are excipients added to facilitate the tablet manufacturing process, particularly the tablet manufacturing process involving granule compression. Glidants can promote the fluidity of granules and/or powders, facilitating filling into molds, reducing friction between the granules and/or powder particles themselves and between the mold, punch, granules, and powder, and facilitating tablet compression and ejection from the mold. Glidants can therefore prevent tablet compounds and tablets from sticking to the tablet press punch and mold. Glidants used in tablet formulation include magnesium stearate, calcium behenate, glycerol monostearate, stearic acid, sodium stearyl fumarate, talc, hydrated vegetable fats such as hydrogenated castor oil, hydrogenated cottonseed oil, and mixtures thereof. Preferred glidants in the present invention are magnesium stearate and/or sodium stearyl fumarate.

Magnesium stearate (CAS No. 557-04-0) is a magnesium salt of stearic acid, found in lime soap. Magnesium stearate is a salt composed of a magnesium ion (Mg ²⁺ ) and two stearate units. Magnesium stearate is water-insoluble. It has a layered crystal structure that reduces internal friction and a very small particle size of 3-15 ㎛. Therefore, magnesium stearate is highly suitable as a lubricant because it attaches to the surfaces of other particles in molecular mixtures, reducing interparticle friction and friction with the external surface.

Sodium stearyl fumarate (CAS No. 4070-80-8) is synthetically produced by the reaction between stearyl alcohol and maleic anhydride. The product of this reaction is then isomerized to form a salt, yielding sodium stearyl fumarate. Sodium stearyl fumarate is used as a lubricant in oral pharmaceutical formulations and is generally considered non-toxic and non-irritating.

In embodiments of the present invention, a binder binds the components together into a tablet, and is preferably used within the granules during wet granulation. The binder is used during granulation and directly during tablet compression to increase the cohesion of powder particles or granules during compression, thereby ensuring that tablets and granules can be formed with the required mechanical strength and specified hardness. The binder may also be used as a processing aid during the granulation process. The binder is preferably a macromolecular polar amorphous material that, due to its amorphous nature, exhibits isotropic deformation behavior and provides optimal conditions for flowing into any available cavities during compression.

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 a natural polymer binder or salt thereof, including starch, processed or pretreated starch or starch salts, or an inorganic binder, such as corn starch, potato starch, sodium starch, pregelatinized starch; alginic acid or a salt thereof, such as sodium alginate; gelatin; guar gum; gum arabic; candelilla wax; carnauba wax, dextrans, sugars and hexicols, such as lactose, mannitol, saccharose and inorganic calcium compounds, such as calcium hydrogen phosphate and tribasic calcium phosphate.

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 starch such as dextran and maltodextrin, hydroxypropyl starch, hydroxypropyl cellulose (HPC, hypromellose), hydroxypropyl methyl cellulose (HPMC, hypromellose), methyl cellulose (MC) and sodium carboxymethyl cellulose.

In the context of the present invention, the expression “polymer binder” refers to a fully 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 copolymer (commercially available as Soluplus ^® ), polyethylene glycol-polyvinyl alcohol graft copolymer (PEG-PVA), povidone (PVP) and copovidone.

The binder may be present in the pharmaceutical composition as a single component/ingredient or as a mixture of components/ingredients. Preferred binders according to the present invention are povidone, covidone, and/or corn starch.

Povidone, also known as "polyvinylpyrrolidone" (PVP), refers to a linear polymer of N-vinyl-2-pyrrolidone, also known as 1-vinyl-2-pyrrolidone. Povidone can encompass polymerized products with various molecular sizes or chain lengths. Overall, the molecular weight spectrum ranges from 10,000 to 350,000 Da. Povidone typically exists as a white to yellowish-white, highly hygroscopic, odorless powder or flake, and is readily soluble in water and in polar organic solvents such as alcohol, glycol, and glycerol.

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

In the present invention, a surfactant (also referred to as a surface-active agent, or wetting agent, emulsifier, or suspending agent) is a substance that adsorbs to the surface or interface of a system and lowers the surface tension of the medium in which it is dissolved and/or the interfacial tension with other phases. Surfactants are typically organic compounds that are amphiphilic, meaning that they have a polar or hydrophilic (i.e., water-soluble) portion and a non-polar (i.e., hydrophobic or lipophilic) portion. The hydrophobic portion of most surfactants is very similar and consists of a hydrocarbon chain that may be branched, linear, or aromatic. Surfactant molecules have one or two tails; those with two tails are called di-chain. Most commonly, surfactants are classified according to their hydrophilic portion. The hydrophilic portion may be anionic, cationic, amphoteric, or non-ionic 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 Book of Prof. Tharwat F. Tadros (Applied Surfactants: Principles and Applications; First published: 26 January 2005; Print ISBN:9783527306299; Online ISBN:9783527604814; DOI:10.1002/3527604812).

Suitable surfactants according to the present invention include sodium lauryl sulfate (SLS), sucrose laurate, macrogolglycerol ricinoleate (commercially available as Kolliphor ^® EL), polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (commercially available as Tween ^® 20, 40, 60 and 80), polyoxyethylated oleic glycerides, polyoxyethylated glycol monoethers, polyoxyl 40 hydrogenated castor oil, polyethoxylated alkyl ethers (Brijs ^® 35, 56, 78), lauroyl macrogol glycerides (Gelucire 44/14), polyethoxylated fatty acid esters (Myrj ^® 52, Solutol ^® HS15), polyethoxylated glycerides. (caprylo/caproyl macrogolglycerides: Labrasol ^® ), polyoxyl castor oil derivatives (polyoxyl 35 castor oil: Cremophor ^® EL, polyoxyethylene polyoxypropylene block copolymers (poloxamers, e.g. Poloxamer ^® 188, Poloxamer ^® 40, Kollisolv ^® P 124 (Poloxamer 124 NF/EP)), saturated polyglycolated glycerides (lauroyl macrogolglycerides: Gelucire ^® 44/14 (lauroyl polyoxyl-32 glycerides), stearoyl macrogolglycerides: Gelucire ^® 50/13), Labrasol ^® ALF (caprylocaproyl macrogol-8 glycerides), linoleic macroglycerides, mixed glycerides of long-chain fatty acids (Gelucire 33/01), oleic acid, Surfactants may include, but are not limited to, glyceryl monostearate, lecithin, phosphatidylcholine and phosphatidylcholine mixtures (e.g., propylene glycol, medium chain triglycerides, phosphatidylcholine mixtures in ethanol), unsaturated polyglycolized glycerides (macrogolglycerides, e.g., Labrafil ^® M1944 CS, Labrafil ^® M2125CS), sorbitan esters (e.g., sorbitan monooleate (Span ^® 80) and sorbitan monolaurate (Span ^® 20)), and polyethoxylated alkyl ethers (Brijs ^® 30, 52, 72) and mixtures thereof. Preferred surfactants in the present invention include, but are not limited to, sodium lauryl sulfate (SLS, also known as sodium dodecyl sulfate or SDS), poloxamer 188, sucrose laurate (also known as sucrose lauric acid ester). (including polysorbate 20, polysorbate 80, sorbitan monolaurate, sorbitan monooleate, or mixtures thereof). The product names/trademarks disclosed herein are generally accepted as synonyms for the corresponding chemical compounds, and the chemical names of the corresponding compounds can also be confirmed by referring to the technical information for the corresponding product.

Additionally, the composition of the present invention may also include other excipients such as pigments and/or excipients, as desired.

Antioxidants are chemical compounds that slow down or completely prevent the oxidation of other substances in a pharmaceutical composition, such as the active ingredient or excipients. Depending on their chemical mechanism of action, antioxidants can be classified as radical scavengers, reducing agents, and antioxidant synergists. Radical scavengers are often compounds with sterically hindered phenolic groups that terminate oxidation reactions by forming inactive, stable radicals that do not react further. Radical scavengers include, but are not limited to, tocopherols, tocopherol acetate, tocotrienols, polyphenol compounds (e.g., flavonoids, anthocyanins, phytoestrogens, nordihydroguaiaretic acid), carotenoids (e.g., lycopene, beta-carotene, and lutein), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and gallates (e.g., ethyl gallate, propyl gallate, octyl gallate, and dodecyl gallate). Reducing agents have a low redox potential, making them more likely to be oxidized than the substance they are protecting. Reducing agents include, but are not limited to, ascorbic acid, sulfites, and organic sulfur-containing compounds (e.g., glutathione, cysteine, and thiolactic acid). Antioxidant enhancers enhance the effectiveness of antioxidants, for example, by regenerating depleted antioxidants. Enhancers can enhance the antioxidant effects of radical scavengers or reducing agents by forming complexes with trace metals or by maintaining an oxidation-inhibiting pH. Examples of antioxidant enhancers include sodium edetate.

The most commonly used pharmaceutical solid dosage forms today include granules, pellets, tablets, and capsules. Tablets are pharmaceutical solid dosage forms manufactured by extrusion or molding, containing the drug substance along with one or more excipients.

Tablet manufacturing methods include direct compression (direct tableting) and granulation followed by compression, such as wet and dry granulation. Tablet compression is performed using a high-speed mechanical device called a tablet press. Two types of tablet presses are commonly used, including eccentric presses and rotary presses. Both have two movable punches (bottom and top punches) per functional unit, as well as a mold and hopper. These types of presses and their uses are well known to those skilled in the art. The present invention preferably encompasses wet granulation and subsequent tablet manufacturing processes.

In most cases, active ingredients and excipients are granulated prior to tableting, i.e., powder particles are converted into granules. This results in a product with larger particle sizes and better flowability compared to powder particles. This ensures continuous and uniform filling of the tableting machine mold, resulting in consistent tablet weight and high dosage accuracy. Granules are typically asymmetrical agglomerates of powder particles with irregular geometric shapes, often with uneven, jagged, or rough surfaces, resulting in excellent compressibility. Granulation techniques include wet granulation and dry granulation.

In the present invention, wet granulation is a process of binding together various powder particles using an adhesive and/or a liquid solution. Wet granulation techniques typically involve a granulating liquid, which is preferably a volatile solvent that is easily removed by drying and is non-toxic. The choice of liquid depends on the API and other excipients and can be selected according to the needs of those skilled in the art. Examples of liquids for wet granulation include water, ethanol, isopropanol, or any other aqueous solution. The granulating liquid may further comprise an active pharmaceutical ingredient or excipients. Various granulation techniques, both batch and continuous, can be employed, including, but not limited to, high-shear granulators, fluidized bed granulators, twin-screw granulators, foam granulators, and steam granulators. Wet granulation processes are well known to those skilled in the art and can be adjusted depending on the characteristics of the powder and the available equipment. In a typical wet granulation process, a wet material is forced through a sieve to form wet granules, which are then dried. A subsequent screening step breaks up any granule agglomerates. The granules are then compressed into tablets.

The term "intragranular" or "intragranular phase" refers to a component contained in the granules of a pharmaceutical composition or pharmaceutical composition, i.e. a component used in preparing a mixture to be made into granules, whereas the term "extragranular" or "extragranular phase" refers to an additive or excipient added to the granules, i.e. added to the intragranular phase after the granules have been first made.

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 the granulated dosage form can be very effective if they are used both "intragranularly" and "extragranularly", so that the tablet disintegrates into granules and the granules further disintegrate to release the drug substance into solution. There are three ways to incorporate disintegrants into the tablet: (a) internal addition (intragranularly), (b) external addition (extragranularly), and (b) addition to both sides of the granules (partially internal and externally). In the present invention, the disintegrant is present in the granules or outside the granules or in both of these granule phases, preferably in a weight ratio of 5:1 to 1:5, for example 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.

In the present invention, the term "pharmaceutical 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, for example, in a powder, granules, the intragranular phase of a tablet, a tablet, a tablet prepared by compression of granules, a tablet prepared by direct compression of powders, or a capsule. The pharmaceutical unit may be in the form of, for example, a powder, granules, pellets, tablets, or soft capsules. The pharmaceutical unit may be, in an embodiment, directly administered to a subject as a dosage form, or may be further processed to prepare a dosage form for administration to a subject, for example, by compressing granules into tablets. In an embodiment, the pharmaceutical unit is a final dosage form suitable for administration to a subject. In an embodiment, the pharmaceutical unit is a granule, i.e., a single granule phase. In the present invention, the active ingredients netupitant and palonosetron or a salt or hydrate thereof are present in a single pharmaceutical unit, preferably in granules, more preferably in the intragranular phase of a tablet manufactured by compressing granules.

The terms "fixed dose" and "fixed dose combination" refer to a pharmaceutical composition containing one or more active ingredients in a specified amount in a single 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.

The present invention is described with reference to the drawings, which provide a detailed description supporting potentially preferred non-limiting embodiments of the invention.
Figure 1: Comparison of the dissolution of netupitant measured in Example E2 and the reference product Akynzeo ^®.
Figure 2: Comparison of the dissolution of palonosetron measured in Example E2 and the reference product Akynzeo ^® .
Figure 3: Comparison of dissolution of netupitant measured in Example E3 and the reference product Akynzeo ^® .
Figure 4: Comparison of the dissolution of palonosetron hydrochloride measured in Example E3 and the reference product Akynzeo ^® .
Figure 5: Comparison of the dissolution of netupitant measured in Example E30 and the reference product Akynzeo ^® .
Figure 6: Comparison of the dissolution of palonosetron hydrochloride measured in Example E30 and the reference product Akynzeo ^® .
Figure 7: Photograph of a tablet manufactured according to Example E2. The tablet weighs 450 mg, is 6.09-6.16 mm thick, is 7.5 mm wide, and is 14 mm long.
Figure 8: Comparison of dissolution of netupitant measured in Example E31 and the reference product Akynzeo ^® .
Figure 9: Comparison of the dissolution of palonosetron hydrochloride measured in Example E31 and the reference product Akynzeo ^® .
Figure 10: Comparison of the dissolution of netupitant measured in Example E32 and the reference product Akynzeo ^® .
Figure 11: Comparison of the dissolution of palonosetron hydrochloride measured in Example E32 and the reference product Akynzeo ^® .
Figure 12: Comparison of dissolution of netupitant measured in Example E33 and the reference product Akynzeo ^® .
Figure 13: Comparison of the dissolution of palonosetron hydrochloride measured in Example E33 and the reference product Akynzeo ^® .

Example

The present invention is illustrated by the examples described herein. These examples provide technical support for the detailed description supporting potentially preferred, non-limiting embodiments of the present invention.

Part A - General Manufacturing Procedures

General manufacturing procedure using wet granulation process (GP1):

1. distribution:

1.1. All materials are distributed according to the material specifications.

2. constitution:

2.1. Sift the top-A materials together through an ASTM #20 mesh.

3. Prepare the API solution:

3.1. Dissolve the ingredients in Phase B in purified water.

4. Granulation:

4.1. Step 2.1 Granulate the material with the API solution from Step 3.1 using a rapid mixer granulator.

5. dry:

5.1. Step 4.1 Dry the material in a rapid dryer.

6. smash:

6.1. Step 5.1 The material is ground using a Quadrosa co-mill equipped with a 40G screen.

7. Ingredients other than granules:

7.1. Sieve the C material through an ASTM #35 mesh.

8. mix:

8.1. Mix the materials from Step 6.1 and Step 7.1 using a suitable blender.

9. compression:

9.1. Compress the mixture of the lubricant from Step 8.1 using a suitable punch.

General manufacturing procedure using dry granulation process (GP2):

1. distribution:

1.1. All materials are distributed according to the material specifications.

2. constitution:

2.1. Palonosetron HCl IH and cellulose, microcrystalline (Vivapur ^® 102) are sieved together through ASTM #30 mesh.

3. mix:

3.1. Step 2.1 Mix the materials using a suitable blender.

4. constitution:

4.1. Sieve the materials from Step 3.1 and Phase B together through an ASTM #20 mesh.

5. mix:

5.1. Step 4.1 Mix the materials using a suitable blender.

6. Dry granulation:

6.1. Step 5.1 Granulate the material using a Chilsonator under appropriate parameters.

7. smash:

7.1. Step 6.1 Grind the material in an OG mill or Chilsonator mill equipped with a 1.0 mm screen.

8. Ingredients other than granules:

8.1. Sieve the C material through an ASTM #35 mesh.

9. mix:

9.1. Step 6.1 Mix the materials from Step 5.1 with those from Step 6.1 using a suitable blender.

10. compression:

10.1. Compress the mixture of the lubricant from Step 7.1 using a suitable punch.

General manufacturing procedure using direct compression process (GP3):

1. distribution:

1.1. All materials are distributed according to the material specifications.

2. constitution:

2.1. Palonosetron HCl IH and cellulose, microcrystalline (Vivapur ^® 102) were co-sieved through ASTM #30 mesh and then re-sieved through ASTM #30 mesh.

3. mix:

3.1. Step 2.1 Mix the materials using a suitable blender.

4. smash:

4.1. Step 3.1: Grind the material and the phase-B material together through an appropriate comil screen.

5. mix:

5.1. Step 4.1 Mix the materials using a suitable blender.

6. constitution:

6.1. Sieve the magnesium stearate through an ASTM #35 mesh.

7. mix:

7.1. Step 6.1 Mix the materials and Step 5.1 using a suitable blender.

8. compression:

8.1. Step 7.1 Compress the mixed mixture using a suitable punch.

Part B - Embodiments of the Invention

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.

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 88.09 19.58 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 21:00 4.67 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 88.09 19.58 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 21:00 4.67 4 Poloxamer 188 Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E3 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs, the composition of the present invention. The binder povidone is disposed in the intragranular phase, and the disintegrant croscarmellose sodium is distributed in the intragranular phase and the extragranular phase at a weight ratio of 50:50.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 103.09 22.91 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 21:00 4.67 4 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 4.50 1.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 73.09 16.24 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 31.50 7.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 6.75 1.50 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 6.75 1.50 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 73.09 16.24 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 22.50 5.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.50 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.50 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 73.09 16.24 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 13.50 3.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 15.75 3.50 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 15.75 3.50 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 91.09 20.24 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 13.50 3.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 6.75 1.50 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 6.75 1.50 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 55.09 12.24 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 31.50 7.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 15.75 3.50 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 15.75 3.50 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E9 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs, and microcrystalline cellulose and mannitol as fillers in a 50:50 weight ratio, the composition of the present invention. The binder povidone is disposed in the intragranular phase, and the disintegrant croscarmellose sodium is distributed in the intragranular phase and the extragranular phase in a 50:50 weight ratio.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 60.00 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 64.72 12.94 3 Mannitol (Pearlitol ^® 25C) Ph. Eur. filler 64.72 12.94 4 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 20.00 4.00 5 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.00 6 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.11 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 10.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 5.00 1.00 Tablet weight (mg): 500.00 100.00

Example E10 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet manufactured by wet granulation, comprising netupitant and palonosetron as APIs, and microcrystalline cellulose and mannitol as fillers in a weight ratio of 1:3, according to the composition of the present invention. The binder povidone was disposed in the intragranular phase, and the disintegrant croscarmellose sodium was distributed in the intragranular phase and the extragranular phase in a weight ratio of 50:50.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 60.00 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 32.36 6.74 3 Mannitol (Pearlitol ^® 25C) Ph. Eur. filler 97.08 19.42 4 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 20.00 4.00 5 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.00 6 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.11 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 10.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 5.00 1.00 Tablet weight (mg): 500.00 100.00

Example E11 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs, and microcrystalline cellulose and mannitol as fillers in a 3:1 weight ratio, the composition of the present invention. The binder povidone was disposed in the intragranular phase, and the disintegrant croscarmellose sodium was distributed in the intragranular phase and the extragranular phase in a 50:50 weight ratio.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 60.00 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 97.08 19.42 3 Mannitol (Pearlitol ^® 25C) Ph. Eur. filler 32.36 6.47 4 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 20.00 4.00 5 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.00 6 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.11 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 10.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 5.00 1.00 Tablet weight (mg): 500.00 100.00

Example E12 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs, and microcrystalline cellulose and mannitol as fillers in a 50:50 weight ratio, the composition of the present invention. The binder povidone was placed in the intragranular phase, and the disintegrant croscarmellose sodium was distributed in the intragranular and extragranular phases in a 50:50 weight ratio. The binder povidone and the surfactant sodium lauryl sulfate were used in lower concentrations.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 60.00 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 77.22 15.44 3 Mannitol (Pearlitol ^® 25C) Ph. Eur. filler 77.22 15.44 4 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 5.00 1.00 5 Sodium Lauryl Sulfate Ph. Eur. surfactant 5.00 1.00 6 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.11 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 10.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 10.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 5.00 1.00 Tablet weight (mg): 500.00 100.00

Example E13 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs and polysorbate 20 (Tween ^® 20) as a surfactant, the composition of the present invention. The binder povidone was disposed in the intragranular phase, and the disintegrant croscarmellose sodium was distributed in a 50:50 weight ratio between the intragranular phase and the extragranular phase. The surfactant was disposed in the binder solution.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 18:00 4.00 4 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 Polysorbate 20 (Tween ^® 20) Ph. Eur. surfactant 15.00 3.33 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E14 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs and polysorbate 80 (Tween ^® 80) as a surfactant, the composition of the present invention. The binder povidone was disposed in the intragranular phase, and the disintegrant croscarmellose sodium was distributed in a 50:50 weight ratio between the intragranular phase and the extragranular phase. The surfactant was disposed in the binder solution.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 18:00 4.00 4 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 Polysorbate 80 (Tween ^® 80) Ph. Eur. surfactant 15.00 3.33 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E15 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs and sorbitan monolaurate (Span ^® 20) as a surfactant, the composition of the present invention. The binder povidone was disposed in the intragranular phase, and the disintegrant croscarmellose sodium was distributed in a 50:50 weight ratio between the intragranular phase and the extragranular phase. The surfactant was disposed in the binder solution.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 18:00 4.00 4 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 Sorbitan monolaurate (Span ^® 20) Ph. Eur. surfactant 15.00 3.33 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E16 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs and sorbitan monooleate (Span ^® 80) as a surfactant, the composition of the present invention. The binder povidone was disposed in the intragranular phase, and the disintegrant croscarmellose sodium was distributed in a 50:50 weight ratio between the intragranular phase and the extragranular phase. The surfactant was disposed in the binder solution.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 18:00 4.00 4 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 Sorbitan monooleate (Span ^® 80) Ph. Eur. surfactant 15.00 3.33 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E17 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs and sodium lauryl sulfate as a surfactant, the composition of the present invention. The binder povidone is positioned in the intragranular phase, and the disintegrant croscarmellose sodium is positioned in the extragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 18:00 4.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 18:00 4.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 18:00 4.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 18:00 4.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 2 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 18:00 4.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Sodium Starch Glycolate Ph. Eur. disintegrant 9.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Sodium Starch Glycolate Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Core Tablet Weight (mg): 450.00 100.00

Example E20 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet manufactured by wet granulation, comprising netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, and crospovidone Type A (Polyplasdone ^® XL) as a disintegrant, the composition of the present invention. The binder povidone was disposed in the intragranular phase, and the disintegrant crospovidone Type A (Polyplasdone ^® XL) was distributed in the intragranular phase and the extragranular phase at a weight ratio of 50:50.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 6.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.9 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 18:00 4.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Crospovidone Type A (Polyplasdone ^® XL) Ph. Eur. disintegrant 9.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. Phase C (Activation and Mixing): 1 Crospovidone Type A (Polyplasdone ^® XL) Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 18:00 4.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Pregelatinized starch Ph. Eur. disintegrant 9.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Pregelatinized starch Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E22 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs and sodium lauryl sulfate as a surfactant, the composition of the present invention. The binder povidone was distributed in a 50:50 weight ratio between the intragranular phase and the extragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 9.00 2.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 Povidone K30 (Plasdone ^® K-29/32) Ph. Eur. binder 9.00 2.00 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E23 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, and copovidone as a binder, the composition of the present invention. The binder povidone is disposed in the intragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Kollidon ^® VA64 Ph. Eur. binder 18:00 4.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E24 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, and corn starch as a binder, the composition of the present invention. The binder povidone is disposed in the intragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 84.94 18.88 3 Corn starch Ph. Eur. binder 18:00 4.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E25 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet manufactured by dry granulation, comprising netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, and corn starch as a binder, the composition of the present invention.

S. No. ingredient function mg/tablet Refined weight % Top-A (Mixed): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 Cellulose, microcrystalline (Vivapur ^® 102) Ph. Eur. filler 80.44 17.88 Phase B (Mixed & Compressed): 1 Netupitant In-house API 300.00 67.67 2 Povidone Ph. Eur. binder 18:00 4.00 3 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 4 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 5 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Top-C (Active): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E26 - Netupitant/palonosetron 300 mg/0.5 mg tablets: A tablet manufactured by direct compression, comprising netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, and corn starch as a binder, the composition of the present invention.

S. No. ingredient function mg/tablet Refined weight % Top-A (Mixed): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 Cellulose, microcrystalline (Vivapur ^® 102) Ph. Eur. filler 84.94 18.88 Phase B (Mixed & Co-Crushed): 1 Netupitant In-house API 300.00 67.67 2 Povidone Ph. Eur. binder 18:00 4.00 3 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 4 Croscarmellose Sodium Ph. Eur. disintegrant 18:00 4.00 5 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 Phase C (Mixed): 1 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

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

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 80.44 17.88 3 Povidone Ph. Eur. binder 18:00 4.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E28 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet manufactured by wet granulation, comprising netupitant and palonosetron as APIs, sodium lauryl sulfate as a surfactant, and sodium stearyl fumarate and magnesium stearate as lubricants, the composition of the present invention. The lubricant sodium stearyl fumarate is disposed in the intragranular phase, and the lubricant magnesium stearate is disposed in the extragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 80.44 17.88 3 Povidone Ph. Eur. binder 18:00 4.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 15.00 3.33 5 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 9.00 2.00 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E29 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet prepared by wet granulation, comprising netupitant and palonosetron as APIs, polysorbate 80 (Span ^® 80) as a surfactant, mannitol and microcrystalline cellulose as fillers, and sodium stearyl fumarate as a lubricant, the composition of the present invention. The filler mannitol is disposed in the intragranular phase, and the filler microcrystalline cellulose is disposed in the extragranular phase. The lubricant sodium stearyl fumarate is disposed in the extragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.00 66.67 2 Mannitol (Pearlitol ^® 25C) Ph. Eur. filler 30.00 6.67 3 Povidone Ph. Eur. binder 18:00 4.00 4 Croscarmellose Sodium Ph. Eur. disintegrant 14:00 3.11 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 Polysorbate 80 (Tween ^® 80) Ph. Eur. surfactant 15.00 3.33 3 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 49.94 11.10 2 Croscarmellose Sodium Ph. Eur. disintegrant 14:00 3.11 3 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 4.00 0.89 4 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E30 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet manufactured by wet granulation, comprising 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), the composition of the present invention. The lubricant sodium stearyl fumarate is disposed in the intragranular phase, and the lubricant magnesium stearate is disposed in the extragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 302.85 67.30 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 19.89 4.42 4 Mannitol (Pearitol ^® 25C) Ph. Eur. filler 68.20 15.16 3 Povidone Ph. Eur. binder 13.50 3.00 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 4.5 1.00 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.50 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.00 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.57 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.50 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 2.00 3 Magnesium stearate Ph. Eur. lubricant 4.50 1.00 Tablet weight (mg): 450.00 100.00

Example E31 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet manufactured by wet granulation, comprising 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), the composition of the present invention. The lubricant sodium stearyl fumarate is disposed in the intragranular phase, and the lubricant magnesium stearate is disposed in the extragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.96 66.22 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 44.51 9.79 4 Mannitol (Pearitol ^® 25C) Ph. Eur. filler 45.47 10.00 3 Povidone Ph. Eur. binder 13.50 2.97 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 4.5 0.99 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.48 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 0.99 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.48 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 1.98 3 Magnesium stearate Ph. Eur. lubricant 9.00 1.98 Tablet weight (mg): 454.50 100.00

Example E32 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet manufactured by wet granulation, comprising 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), the composition of the present invention. The lubricant sodium stearyl fumarate is disposed in the intragranular phase, and the lubricant magnesium stearate is disposed in the extragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 300.96 66.22 2 Cellulose, microcrystalline (Vivapur ^® 101) Ph. Eur. filler 67.24 14.79 4 Mannitol (Pearitol ^® 25C) Ph. Eur. filler 22.74 5.00 3 Povidone Ph. Eur. binder 13.50 2.97 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 4.5 0.99 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.48 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 0.99 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.12 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.48 2 Colloidal silicon dioxide (Aerosil ^® 200 Pharma) Ph. Eur. Fluidizer 9.00 1.98 3 Magnesium stearate Ph. Eur. lubricant 9.00 1.98 Tablet weight (mg): 454.50 100.00

Example E33 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet manufactured by wet granulation, comprising 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), the composition of the present invention. The lubricant sodium stearyl fumarate is disposed in the intragranular phase, and the lubricant magnesium stearate is disposed in the extragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 302.11 69.21 2 Cellulose, microcrystalline Ph. Eur. filler 16.120 3.69 4 Mannitol Ph. Eur. filler 54.705 12.53 3 Povidone Ph. Eur. binder 13.50 3.09 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 4.5 1.03 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.58 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.03 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.58 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.06 3 Magnesium stearate Ph. Eur. lubricant 9.00 2.06 Tablet weight (mg): 436.50 100.00

Example E34 - Netupitant/Palonosetron 300 mg/0.5 mg Tablets: A tablet manufactured by wet granulation, comprising 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), the composition of the present invention. The lubricant sodium stearyl fumarate is disposed in the intragranular phase, and the lubricant magnesium stearate is disposed in the extragranular phase.

S. No. ingredient function mg/tablet Refined weight % Phase A (granulation): 1 Netupitant In-house API 301.75 69.21 2 Cellulose, microcrystalline Ph. Eur. filler 34.47 7.91 4 Mannitol Ph. Eur. filler 36.22 8.31 3 Povidone Ph. Eur. binder 13.50 3.10 4 Sodium Lauryl Sulfate Ph. Eur. surfactant 4.5 1.03 5 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.58 6 Sodium stearyl fumarate Ph. Eur. lubricant 4.50 1.03 Phase B (API solution): 1 Palonosetron hydrochloride In-house API 0.56 0.13 2 purified water menstruum q. s. - Phase C (Activation and Mixing): 1 Croscarmellose Sodium Ph. Eur. disintegrant 11.25 2.58 2 Colloidal silicon dioxide Ph. Eur. Fluidizer 9.00 2.06 3 Magnesium stearate Ph. Eur. lubricant 9.00 2.06 Tablet weight (mg): 436.00 100.00

For the tablet compression according to Examples E1 - E34, an oval tool of 14.0 X 7.5 or 15.0 X 7.0 was used.

The manufactured tablets had a size of 14 mm x 7.5 mm or 15 mm x 7 mm, respectively, and a thickness of 4.5-6.8 mm.

Part C - Reference Product Features

Table: Physical parameters of reference product Akynzeo ^® 300 mg/0.5 mg capsules

product Akynzeo ^® 300 mg/0.5 mg capsules Common name Netupitant and palonosetron 300/0.5 mg capsules Lot number / batch number 41000954 Expiration date 12/2024 Primary packaging Alu - Alu blister Secondary packaging paperboard explanation A hard gelatin capsule with a white body and a caramel-colored cap, printed with "HE1." Each capsule contains three tablets and one softgel. Average weight of capsules: 655.90 mg Capsule length: 21.2-21.7 mm Capsule diameter: 7.6 mm Average weight of soft capsules: 123.2 mg Average weight of 3 tablets: 435.2 mg Average weight of each tablet: 145.10 mg Tablet diameter: 6.02 mm Refined thickness: 4.17 mm Purified disintegration time: 18 min 29 sec Manufacturer and Marketing Authorization Holder Helsinn Virex Pharmaceuticals Limited (Damastown, 15 Mulhadat, Dublin, Ireland)

Part D - Dissolution Test

Dissolution testing was performed using the United States Pharmacopeia (USP) Apparatus II (paddle) and the following method as recommended for the combination of netupitant and palonosetron hydrochloride in the FDA Dissolution Methods Database on the FDA website:

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

Palonosetron hydrochloride: 500 ml of 0.01 N HCl, paddle speed 75 rpm, QC sampling time 45 min.

Table: Dissolution profile of Akynzeo ^® 300/0.5 mg (B. No: 41000954) in 0.07 M sodium phosphate buffer, pH 6.8 with 1% SDS - netupitant

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - netupitant 1 2 3 4 5 6 average % RSD Paddle, 900 ml, 100 rpm 5 3 4 3 5 4 8 5 41.57 10 22 27 17 23 17 29 23 22.09 15 41 51 41 38 29 47 41 18.46 20 62 69 50 53 44 60 56 16.06 30 82 90 87 75 65 82 80 11.25 45 92 98 98 90 88 96 94 4.56 60 96 98 98 95 95 97 97 1.43 75 98 98 98 98 97 98 98 0.42 90 99 98 99 99 98 98 99 0.56

Table: Dissolution profile of Akynzeo ^® 300/0.5 mg (B. No: 41000954) in 0.01 N HCl - Palonosetron

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - palonosetron 1 2 3 4 5 6 average % RSD Paddle, 500 ml, 75 rpm 5 1 1 1 1 1 2 1 41.00 10 2 2 1 87 10 7 18 188.33 15 71 16 93 97 47 79 67 45.94 20 93 77 98 94 96 84 89 August 21 30 96 93 96 97 94 91 95 2.38 45 96 94 96 97 95 97 96 1.22 60 96 97 96 97 96 97 97 0.57 Inf 96 96 97 98 96 98 97 1.01

Table: Dissolution profile of E2 , i.e., netupitant/palonosetron 300 mg/0.5 mg tablets in 0.07 M sodium phosphate buffer, pH 6.8, with 1% SDS - netupitant

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - netupitant Akynzeo ^® 300/0.5 mg (4100956) E2 %DR %RSD %DR %RSD pH 6.8 0.07 M sodium phosphate buffer with 1% SDS, paddle, 900 ml, 100 rpm 5 5 41.57 40 11.90 10 23 22.09 73 7.70 15 41 18.46 89 1.66 20 56 16.06 94 0.89 30 80 11.25 97 1.09 45 94 4.56 98 1.41 60 97 1.43 98 1.36 75 98 0.42 98 1.06 90 98 0.56 98 1.40

For the tablets of Akynzeo ^® and Example E2, netupitant was observed to be completely released after 75 minutes with a drug release rate of greater than 95%.

According to the FDA guidance "Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on the Biopharmaceutical Classification System," dissolution was considered highly variable if the relative standard deviation (RSD) exceeded 20% at 10 minutes or less and 10% thereafter.

The netupitant dissolution results of Akynzeo ^® at pH 6.8 showed high variability up to 30 minutes, whereas Example E2 of the present invention showed low variability.

Table: Dissolution profile of netupitant/palonosetron 300 mg/0.5 mg tablets of E2 in 0.01 N HCl - palonosetron

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - palonosetron Akynzeo ^® 300/0.5 mg (4100956) E2 %DR %RSD %DR %RSD 0.01 N HCl, paddle, 500 ml, 75 rpm 5 1 41.00 75 4.80 10 18 188.33 101 1.50 15 67 45.94 101 1.77 20 89 August 21 101 1.16 30 95 2.38 102 1.49 45 96 1.22 101 1.36 60 97 0.57 101 1.61 Rec 97 1.01 102 1.60

For the tablets of Akynzeo ^® and Example E2, palonosetron was observed to be completely released after 45 minutes with a drug release rate of more than 95%.

The dissolution results of palonosetron in Akynzeo ^® in 0.01 N HCl medium showed very high variability up to 15 minutes, whereas Example E2 of the present invention showed low variability.

Table: Dissolution profile of netupitant/palonosetron 300 mg/0.5 mg tablets of E3 in 0.07 M sodium phosphate buffer, pH 6.8, containing 1% SDS - netupitant

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - netupitant Akynzeo ^® 300/0.5 mg (4100956) E3 %DR %RSD %DR %RSD pH 6.8 0.07 M sodium phosphate buffer with 1% SDS, paddle, 900 ml, 100 rpm 5 5 41.57 20 7.78 10 23 22.09 48 5.19 15 41 18.46 77 3.16 20 56 16.06 92 0.88 30 80 11.25 103 0.50 45 94 4.56 107 0.97 60 97 1.43 107 1.02 75 98 0.42 108 0.78

For the tablets of Akynzeo ^® and Example E3, netupitant was observed to be completely released after 75 minutes with a drug release rate of greater than 95%. The dissolution results of Example E3 showed low variability.

Table: Dissolution profile of netupitant/palonosetron 300 mg/0.5 mg tablets of E3 in 0.01 N HCl - palonosetron

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - palonosetron Akynzeo ^® 300/0.5 mg (4100956) E3 %DR %RSD %DR %RSD 0.01 N HCl, paddle, 500 ml, 75 rpm 5 1 41.00 45 3.86 10 18 188.33 86 3.71 15 67 45.94 113 0.91 20 89 August 21 114 0.90 30 95 2.38 115 0.73 45 96 1.22 115 0.73 60 97 0.57 115 0.71

For the tablets of Akynzeo ^® and Example E3, palonosetron was observed to be completely released after 45 minutes with a drug release rate of more than 95%. The dissolution results of Example E3 showed low variability.

Table: Dissolution profile of netupitant/palonosetron 300 mg/0.5 mg tablets at E30 in 0.07 M sodium phosphate buffer, pH 6.8, with 1% SDS - netupitant

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - netupitant Akynzeo ^® 300/0.5 mg (4100956) E30 %DR %RSD %DR %RSD pH 6.8 0.07 M sodium phosphate buffer with 1% SDS, paddle, 900 ml, 100 rpm 5 5 41.57 36 15.4 10 23 22.09 59 16.49 15 41 18.46 82 4.59 20 56 16.06 90 2.51 30 80 11.25 96 1.22 45 94 4.56 101 1.16 60 97 1.43 102 1.24 75 98 0.42 102 1.19 Rec 98 0.56 103 1.6

For tablets of Akynzeo ^® and Example E30, netupitant was observed to be completely released after 75 minutes with a drug release rate of greater than 95%. The dissolution results 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

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - palonosetron Akynzeo ^® 300/0.5 mg (4100956) E30 %DR %RSD %DR %RSD 0.01 N HCl, paddle, 500 ml, 75 rpm 5 1 41.00 49 5.97 10 18 188.33 92 4.59 15 67 45.94 103 1 20 89 August 21 103 1 30 95 2.38 103 1.13 45 96 1.22 104 1.13 60 97 0.57 104 0.61

For tablets of Akynzeo ^® and Example E30, palonosetron was observed to be completely released after 45 minutes with a drug release rate of more than 95%. The dissolution results of Example E30 showed low variability.

Table: Dissolution profile of netupitant/palonosetron 300 mg/0.5 mg tablets of E31 in 0.07 M sodium phosphate buffer, pH 6.8, with 1% SDS - netupitant

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - netupitant Akynzeo ^® 300/0.5 mg (4100956) E31 %DR %RSD %DR %RSD pH 6.8 0.07 M sodium phosphate buffer with 1% SDS, paddle, 900 ml, 100 rpm 5 5 41.57 14 9.04 10 23 22.09 24 15.52 15 41 18.46 39 18.04 20 56 16.06 58 16.4 30 80 11.25 81 7.87 45 94 4.56 95 2.17 60 97 1.43 100 0.89 75 98 0.42 102 0.74 Rec 98 0.56 103 0.96

For the tablets of Akynzeo ^® and Example E31, netupitant was observed to be completely released after 75 minutes with a drug release rate of greater than 95%. The dissolution results of Example E31 showed lower variability compared to Akynzeo ^® .

Table: Dissolution profile of netupitant/palonosetron 300 mg/0.5 mg tablets of Example E31 in 0.01 N HCl - palonosetron

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - palonosetron Akynzeo ^® 300/0.5 mg (4100956) E31 %DR %RSD %DR %RSD 0.01 N HCl, paddle, 500 ml, 75 rpm 5 1 41.00 38 21.51 10 18 188.33 75 8.56 15 67 45.94 90 3.91 20 89 August 21 96 1.47 30 95 2.38 99 2.00 45 96 1.22 99 1.77 60 97 0.57 99 1.90

For the tablets of Akynzeo ^® and Example E31, complete release of palonosetron was observed after 45 minutes with a drug release rate of greater than 95%. The dissolution results for Example E31 demonstrate low variability.

Table: Dissolution profile of netupitant/palonosetron 300 mg/0.5 mg tablets of E32 in 0.07 M sodium phosphate buffer, pH 6.8, with 1% SDS - netupitant

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - netupitant Akynzeo ^® 300/0.5 mg (4100956) E32 %DR %RSD %DR %RSD pH 6.8 0.07 M sodium phosphate buffer with 1% SDS, paddle, 900 ml, 100 rpm 5 5 41.57 14 11.23 10 23 22.09 24 15.37 15 41 18.46 44 16.2 20 56 16.06 62 10.5 30 80 11.25 82 4.79 45 94 4.56 93 2.15 60 97 1.43 97 1.6 75 98 0.42 99 1.89 Rec 98 0.56 100 1.47

For the tablets of Akynzeo ^® and Example E32, netupitant was observed to be completely released after 75 minutes with a drug release rate of greater than 95%. The dissolution results of Example E32 showed lower variability compared to Akynzeo ^® .

Table: Dissolution profile of netupitant/palonosetron 300 mg/0.5 mg tablets of Example E32 in 0.01 N HCl - palonosetron

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - palonosetron Akynzeo ^® 300/0.5 mg (4100956) E32 %DR %RSD %DR %RSD 0.01 N HCl, paddle, 500 ml, 75 rpm 5 1 41.00 27 2.34 10 18 188.33 44 11.22 15 67 45.94 69 9.89 20 89 August 21 83 7.88 30 95 2.38 93 3.93 45 96 1.22 98 1.92 60 97 0.57 99 1.06

For the tablets of Akynzeo ^® and Example E32, palonosetron was observed to be completely released after 45 minutes with a drug release rate of more than 95%. The dissolution results of Example E32 showed low variability.

Table: Dissolution profile of netupitant/palonosetron 300 mg/0.5 mg tablets of E33 in 0.07 M sodium phosphate buffer, pH 6.8, with 1% SDS - netupitant

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - netupitant Akynzeo ^® 300/0.5 mg (4100956) E33 %DR %RSD %DR %RSD pH 6.8 0.07 M sodium phosphate buffer with 1% SDS, paddle, 900 ml, 100 rpm 5 5 41.57 14 11.18 10 23 22.09 22 5.17 15 41 18.46 31 12:35 20 56 16.06 45 3.37 30 80 11.25 68 8.82 45 94 4.56 90 2.81 60 97 1.43 95 0.61 75 98 0.42 99 1.54

For the tablets of Akynzeo ^® and Example E33, netupitant was observed to be completely released after 75 minutes with a drug release rate of greater than 95%. The dissolution results of Example E33 showed lower variability compared to Akynzeo ^® .

Table: Dissolution profile of netupitant/palonosetron 300 mg/0.5 mg tablets of Example E33 in 0.01 N HCl - palonosetron

Dissolution conditions Time (minutes) % of cumulative dissolved content indicated - palonosetron Akynzeo ^® 300/0.5 mg (4100956) E33 %DR %RSD %DR %RSD 0.01 N HCl, paddle, 500 ml, 75 rpm 5 1 41.00 26 2.25 10 18 188.33 38 9.88 15 67 45.94 60 7.26 20 89 August 21 75 3.37 30 95 2.38 89 3.96 45 96 1.22 102 0.98 60 97 0.57 104 0.96

For the tablets of Akynzeo ^® and Example E33, palonosetron was observed to be completely released after 45 minutes with a drug release rate of more than 95%. The dissolution results of Example E33 showed low variability.

All formulations of Examples E2, E3, E30, E31, E32, and E33 of the present invention exhibited dissolution rates of greater than 75% after 75 minutes for netupitant and greater than 75% after 45 minutes for palonosetron hydrochloride in the corresponding quality control (QC) dissolution media, meeting regulatory standard QC testing. The dissolution of the formulations of the present invention was comparable to that of a commercially available reference product (Akynzeo ^® ).

At pH 6.8, the dissolution results of netupitant in Akynzeo ^® showed high variability up to 30 minutes, whereas the dissolution results of the formulations E2, E3, E30, E31, E32 and E33 of the present invention demonstrated low drug release variability for netupitant compared to Akynzeo ^® . The dissolution results of palonosetron in 0.01 N HCl medium in Akynzeo ^® showed very high variability up to 15 minutes, whereas the dissolution results of the formulations E2, E3, E30, E31, E32 and E33 of the present invention demonstrated low variability for palonosetron drug release.

Part E - Content Uniformity of Palonosetron

A content uniformity evaluation was performed on the tablets according to the present invention. Formulations according to Examples E1, E2 , and E32 were used.

B. No. E1 E2 E32 sample analyze % analyze % analyze % 1 102 98.3 99.5 2 103 96.8 101.5 3 99 92.6 98.8 4 101.3 94.7 99.7 5 100.9 94.5 99.8 6 97.1 96.2 100.6 7 100.3 97.4 100.9 8 96.3 96.7 103.4 9 99.6 98.8 101.4 10 99.8 94.5 104.6 average 99.9 96.0 101.0 % RSD 2.08 2.02 1.79 Min 96.3 92.6 98.8 Max 103.0 98.8 104.6 AV 4.99 7.16 4.34

As can be observed from the data presented above, the content uniformity of palonosetron in the formulations according to the present invention was confirmed to be within the specification limits according to European Pharmacopoeia 2.9.40. To ensure consistency of the dosage unit, each unit of the batch must have a content of the active substance very close to the label indication. A dosage unit is defined as a dosage form containing a single dose or a portion of a dose of an active substance in each dosage unit. The term "uniformity of the dosage unit" is defined as the degree of uniformity of the amount of active ingredient between dosage units. Therefore, the requirements of this regulation can be applied to all active substances constituting a dosage unit containing one or more active substances. The uniformity (in terms of content uniformity) of the dosage form was evaluated according to European Pharmacopoeia 2.9.40.

According to the EPAR of the reference product Akynzeo ^® , integrated formulations containing netupitant and palonosetron in a single solid dosage form have poor content uniformity, particularly due to the large dose difference between the active ingredients (300 vs. 0.5 mg) and the differences in physicochemical properties between netupitant and palonosetron. The formulations of the present invention show an improvement over prior art such as the reference product Akynzeo ^® by providing high content uniformity between formulations and the ability to integrate netupitant and palonosetron into a single solid pharmaceutical unit.

Part F - Stability Testing:

The various formulations were packaged in Alu-Alu blisters and stored for 6 months at 40°C/75% RH (ICH accelerated conditions) and 25°C/60% RH (ICH long-term conditions) according to ICH guideline Q1A(R2).

The relative abundance (impurities and/or degradation products) of netupitant and palonosetron were examined initially and after storage under the conditions shown in the table for the respective examples. The relative abundance was detected by HPLC analysis.

Table: Flexible material data for netupitant and palonosetron 300/0.5 mg tablets (Example E1 )

S.No. Impurities Proposed limits E1 (40℃ /75% RH - 6M) E1 (25℃ /60% RH - 6M) 1 Unknown-1 General limit: NMT 0.2 (ICH: NMT 0.4) 0.11 0.16 2 Unknown-2 0.19 0.12 3 Unknown-3 0.12 0.12 4 USP RC-A NMT 1.0 0.23 0.15 % of total impurities 0.65 0.55

Table: Flexible Material Data for Netupitant and Palonosetron 300/0.5 mg Tablets (Example E2 )

S.No. Impurities Proposed limits E2 (40℃/75% RH - 6M) E2 (25℃/60% RH -6M) 1 Unknown-1 General limit: NMT 0.2 (ICH: NMT 0.4) 0.06 0.05 2 Unknown-2 0.12 0.13 3 Unknown-3 0.17 0.17 4 USP RC-A NMT 1.0 0.37 0.15 % of total impurities 0.72 0.50

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

Claims (19)

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. A pharmaceutical composition in the form of a tablet according to claim 1. A pharmaceutical composition according to claim 1 or 2, wherein (a) netupitant or a salt or hydrate thereof and (b) palonosetron or a salt or hydrate thereof are present in the same granule phase. A pharmaceutical composition in claim 3, wherein netupitant and palonosetron are present in combination in the granule phase. A pharmaceutical composition according to any one of claims 1 to 4, wherein the composition comprises a granular phase comprising a filler, a binder and a disintegrant, optionally a lubricant. A 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 croscarmellose sodium, sodium starch glycolate, crospovidone and/or pregelatinized starch, and the lubricant is magnesium stearate and/or sodium stearyl fumarate. A pharmaceutical composition according to any one of claims 1 to 6, wherein the composition comprises an intragranular phase comprising a surfactant. A 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. A pharmaceutical composition according to any one of claims 1 to 8, wherein the composition comprises an extragranular phase comprising a lubricant, a disintegrant, a fluidizing agent, and optionally a filler. A pharmaceutical composition according to claim 9, wherein the lubricant is magnesium stearate and/or sodium stearyl fumarate, the disintegrant is croscarmellose sodium, sodium starch glycolate, crospovidone and/or pregelatinized starch, the fluidizing agent is colloidal silicon dioxide, and the filler is microcrystalline cellulose and/or mannitol. In any one of claims 1 to 10,
Including intragranular and extragranular phases,
A pharmaceutical composition wherein the disintegrant is present in both the intragranular and extragranular phases in a weight ratio of 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. A pharmaceutical composition according to any one of claims 1 to 11, which does not contain an antioxidant. In any one of claims 1 to 12,
i. Intragranular combination comprising:
a) Netupitant or a salt or hydrate thereof, present in a content of 50-75 wt%, preferably 55-70 wt%, more preferably 58-68 wt%,
b) palonosetron or a salt or hydrate thereof, present in a content of 0.05-0.5 wt%, preferably 0.08-0.3 wt%, more preferably 0.1-0.2 wt%,
c) a filler present in a content of 2-40 wt%, preferably 5-35 wt%, more preferably 6-32 wt%,
d) a binder present in a content of 0.1-10 wt%, preferably 0.5-9 wt%, more preferably 0.8-8 wt%,
e) a disintegrant present in a content 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%,
and
ii. Extragranular components including:
a) a lubricant present in a content of 0.1-5 wt%, preferably 0.5-3 wt%, more preferably 0.8-1.5 wt%,
b) optionally, a disintegrant present in a content of 0.1-5 wt%, preferably 0.5-4 wt%, more preferably 0.8-3.8 wt%,
c) optionally, a fluidizing agent present in a content of 0.1-5 wt%, preferably 0.5-3 wt%, more preferably 0.8-2.5 wt%, and
d) optionally, a filler in a content of 1-30 wt%, preferably 5-20 wt%, more preferably 10-15 wt%;
Including,
A pharmaceutical composition wherein the wt% figure is based on the total weight of all components of the tablet. A pharmaceutical composition according to any one of claims 1 to 13, wherein the composition is prepared by the following steps:
i. A step of wet granulating a dry mixture comprising netupitant or a salt or hydrate thereof, a filler, a binder, a disintegrant, optionally a surfactant and/or a glidant, using a solution comprising palonosetron or a salt or hydrate thereof and optionally a surfactant and/or a binder, to produce granules;
ii. A step of mixing the above granules with a lubricant, a disintegrant and a fluidizing agent, and optionally a filler, and
iii. A step of manufacturing tablets by compressing granules treated with a lubricant. A pharmaceutical composition according to any one of claims 1 to 14, wherein the tablet is uncoated. A pharmaceutical composition according to any one of claims 1 to 15, wherein the tablet exhibits at least 75% dissolution of netupitant after 75 minutes in 900 ml of 0.07 M phosphate buffer pH 6.8 containing 1% SDS at a paddle speed of 100 rpm in a dissolution test using USP Apparatus II and/or at least 75% dissolution of palonosetron after 45 minutes in 500 ml of 0.01 N HCl at a paddle speed of 75 rpm in a dissolution test using USP Apparatus II. A pharmaceutical composition according to any one of claims 1 to 16, wherein the tablet exhibits a content uniformity (CU) of 85% to 115% (based on HPLC analysis) and an acceptance value (AV) for palonosetron of less than 15 in the content uniformity test of European Pharmacopoeia (Ph. Eur.) 2.9.40. A pharmaceutical composition according to any one of claims 1 to 17, for use in 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 significantly or moderately emetogenic cancer chemotherapy, such as chemotherapy with cisplatin. A method for preparing a pharmaceutical composition in tablet form, comprising the following steps:
i. A step of wet granulating a dry mixture comprising netupitant or a salt or hydrate thereof, a filler, a binder, a disintegrant, optionally a surfactant and/or a glidant, using a solution comprising palonosetron or a salt or hydrate thereof and optionally a surfactant and/or a binder, to produce granules;
ii. A step of mixing the above granules with a lubricant, a disintegrant and a fluidizing agent, and optionally a filler, and
iii. A step of manufacturing tablets by compressing granules treated with a lubricant.