c12) United States Patent
`Dubewar et al.
`(54) STABLE LIQUID COMPOSITIONS OF
`NETUPITANT AND PALONOSETRON
`(71) Applicant: Slayback Pharma LLC, Princeton, NJ
`(US)
`(72) Inventors: Ashish Anilrao Dubewar, Hyderabad
`(IN); Rahul Dhulaji Bhise, Hyderabad
`(IN); Mahadeo Vasant Mahadik,
`Hyderabad (IN); Shanker Mamidi,
`Nalgonda (IN); Mayur Anshiram
`Adhav, Hyderabad (IN); Raghavender
`Rao Kategher, Vikarabad (IN);
`Nagaraj Gangam, Hyderabad (IN);
`Sumitra Ashokkumar Pillai,
`Hyderabad (IN); Praveen Kumar
`Subbappa, Princeton, NJ (US)
`(73) Assignee: Slayback Pharma LLC, Princeton (IN)
`( *) Notice: Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`(21) Appl. No.: 18/069,204
`(22) Filed:
`(65)
`Dec. 20, 2022
`Prior Publication Data
`US 2023/0190737 Al Jun. 22, 2023
`(30) Foreign Application Priority Data
`Dec. 21, 2021 (IN) ............................. 202141059731
`(51) Int. Cl.
`A61K 311497
`A61K 9/00
`A61K 311473
`(52) U.S. Cl.
`(2006.01)
`(2006.01)
`(2006.01)
`CPC .......... A61K 311497 (2013.01); A61K 9/0019
`(2013.01); A61K 311473 (2013.01)
`( 58) Field of Classification Search
`CPC ... A61K 31/497; A61K 9/0019; A61K 31/473
`See application file for complete search history.
`I 1111111111111111 111111111111111 1111111111 11111 1111111111 111111111111111111
`US012097197B2
`(IO) Patent No.: US 12,097,197 B2
`Sep.24,2024 (45) Date of Patent:
`(56) References Cited
`U.S. PATENT DOCUMENTS
`6,297,375 Bl 2/2001 Bos
`8,426,450 Bl 4/2013 Fadini
`8,951,969 B2 2/2015 Trento
`9,186,357 B2 11/2015 Trento
`9,951,016 B2 4/2018 Bacilieri
`10,624,911 B2 4/2020 Venturini
`2020/0188368 Al * 6/2020 Chandrashekhar ....... A61P 1/08
`2022/0273630 Al 9/2022 Kocherlakota
`OTHER PUBLICATIONS
`Manasa et al. ("International Journal of Advanced Research in
`Medical & Pharmaceutical Sciences" IJARMPS-ISSN-2455-6998)
`vol. 6, Issue.5, Sep.-Oct. 2021. (Year: 2021).*
`* cited by examiner
`Primary Examiner - Jean P Comet
`(74) Attorney, Agent, or Firm - Sarika Singh; McNeely,
`Hare & War LLP
`(57) ABSTRACT
`The present invention relates to stable liquid compositions
`suitable for parenteral administration in the form of a
`solution comprising:
`(a) netupitant and optionally palonosetron;
`(b) at least one pharmaceutically acceptable stabilizer;
`( c) at least one pharmaceutically acceptable solubilizer;
`and
`( d) at least one pharmaceutically acceptable vehicle,
`wherein netupitant is present at a concentration of about
`0.5 mg/mL to about 20 mg/mL and the solution has a
`pH of about 2 to about 6.
`The compositions are suitable for subcutaneous, intrave­
`nous, or intramuscular administration. The invention further
`relates to methods for manufacturing the compositions and
`methods of using such compositions for prevention, treat­
`ment or management of nausea and vomiting.
`24 Claims, No Drawings
`HELSINN EXHIBIT 2009
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00945
`Page 1 of 17
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`US 12,097,197 B2
`1 2
`STABLE LIQUID COMPOSITIONS OF
`NETUPITANT AND PALONOSETRON
`FIELD OF THE INVENTION
`The present invention relates to stable liquid pharmaceu­
`tical compositions comprising netupitant, alone or in com­
`bination with palonosetron, suitable for subcutaneous, intra­
`venous, or intramuscular administration. The invention 10
`further relates to methods for manufacturing the composi­
`tions and methods of using such compositions for preven­
`tion, treatment or management of nausea and vomiting.
`15
`BACKGROUND OF THE INVENTION
`Emesis is the act of vomiting and can be described as the
`forceful expulsion of gastrointestinal contents through the
`mouth brought about by the descent of the diaphragm and
`powerful contractions of the abdominal muscles. Emesis is
`usually, but not always, preceded by nausea. Nausea may be
`defined as a desire to vomit but which is not associated with
`expulsive muscular movement.
`Vomiting and nausea can be caused by several factors
`including anaesthetics, radiation, cancer chemotherapeutic
`agents, toxic agents, medicines (for example serotonin
`reuptake inhibitors, analgesics such as morphine, antibiot­
`ics), pregnancy and surgery.
`Netupitant
`Netupitant is white to off-white crystalline powder. Netu­
`pitant is characterized as a class II compound in the Bio-
`20 pharmaceutical Classification System (BCS), which means
`that it has low aqueous solubility and high permeability.
`Netupitant is very slightly soluble in water (less than 1
`mg/mL). Hence, it is difficult to solubilize netupitant in
`water.
`25 Palonosetron is a selective 5-hydroxytryptamine 3
`(5-HT3 ) antagonist used for the treatment of emesis. The
`chemical name of the hydrochloride salt of Palonosetron is
`(3aS )-2-[ (S)-I-Azabicyclo [2 .2 .2]oct-3-yl ]-2,3,3a,4, 5, 6-
`hexahydro-I-oxo-l Hbemz[ de ]isoquinoline hydrochloride,
`30 as depicted by the following chemical structure:
`Two areas of clinical relevance are nausea and vomiting
`resulting from surgical procedures (post-operative nausea
`and vomiting, or PONY) or chemotherapeutic agents ( che­
`motherapy-induced nausea and vomiting, or CINV) and
`radiation therapy (radiation therapy-induced nausea and 35
`vomiting, or RINV). Symptoms caused by chemotherapeu-
`tic agents such as nausea and vomiting can be so severe that
`the patient refuses further treatment. There are three types of
`emesis associated with the use of chemotherapeutic agents,
`i.e., acute emesis, delayed emesis, and anticipatory emesis. 40
`PONY is also a significant issue for patients and healthcare
`providers. It is rated second to pain as the most feared
`complication by patients and contributes significantly to Palonosetron Hydrochloride
`Palonosetron is white to off-white crystalline powder. anxiety and patient distress.
`Several strategies have emerged in medical community to
`control nausea and vomiting caused by various medical
`procedures or treatment (such as chemotherapy, radiation
`therapy & surgery). With the development of the 5-HT 3
`receptor antagonists in the early 1990s, there emerged new
`strategies in the medical community to better control nausea
`and vomiting caused by various medical procedures, includ­
`ing chemotherapy (CINV), surgery (PONY), and radiation
`therapy (RINV). When added to steroids such as dexam­
`ethasone, several 5-HT 3 antagonists have been demonstrated
`to significantly improve the standard of life for patients
`undergoing emetogenic medical procedures. Examples of
`5-HT 3 antagonists include ondansetron, marketed by
`GlaxoSmithKline, and palonosetron, developed by Helsinn
`Healthcare.
`Netupitant is a potent and selective NK-1 receptor antago­
`nists which has been shown to be highly effective anti­
`emetic in various pre-clinical and clinical models. The
`chemical name of netupitant is 2-[3,5-bis(trifluoromethyl)
`phenyl]-N, 2 dimethyl-N-[ 4-(2-methylphenyl)-6-( 4-meth­
`ylpiperazin-1-yl)pyridin-3-yl]propenamide and its chemical
`structure is represented by the structural Formula:
`45 Palonosetron hydrochloride is characterized as a class I
`compound in the Biopharmaceutical Classification System
`(BCS), which means that it has high aqueous solubility and
`high permeability.
`Netupitant prevents nausea and vomiting during both
`50 acute and delayed phases of emesis, while palonosetron
`prevents nausea and vomiting during acute phase of emesis.
`It has been discovered that palonosetron is much more
`effective in combination with netupitant than with aprepi­
`tant, as reported by Grunberg et al., Support Cancer Care
`55 (2009) 17:589-594. In addition, palonosetron shows an
`improved pharmacokinetic profile ( e.g., better bioavailabil­
`ity) when used in combination with netupitant. Netupitant
`also potentiates the effect of dexamethasone, such that the
`dexamethasone is effective even when administered at sub-
`60 therapeutic doses (i.e., doses at which the dexamethasone
`would be ineffective if administered by itself).
`Solid oral dosage forms have been developed that com­
`bine netupitant and palonosetron for the treatment of acute
`and delayed emesis. An oral product comprising netupitant
`65 and palonosetron has been approved by the Food and Drug
`Administration (FDA) and is marketed by Helsinn Health­
`care in the form of hard gelatin capsules (300 mg netupitant;
`Page 2 of 17
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`US 12,097,197 B2
`3 4
`acute and delayed nausea and vomiting associated with
`initial and repeat courses of highly emetogenic cancer
`chemotherapy.
`No stable liquid formulations of netupitant suitable for
`parenteral administration appear to be available, probably
`because of the poor solubility characteristics exhibited by
`netupitant in aqueous environment. There exists a need for
`liquid formulations of netupitant, alone or in combination
`with palonosetron, suitable for administration by intrave-
`EQ 0.5 mg base palonosetron) under the brand name
`AKYNZEO® (NDA 205718; National Drug Code Number
`69639-101). AKYNZEO® is indicated in combination with
`dexamethasone for the prevention of acute and delayed
`nausea and vomiting associated with initial and repeat
`courses of cancer chemotherapy. Each AKYNZEO® cap­
`sule is composed of one white-caramel hard gelatin capsule
`which contains three tablets each containing 100 mg netu­
`pitant and one gelatin capsule containing 0.5 mg palonose­
`tron (equivalent to 0.56 mg palonosetron hydrochloride).
`Label for AKYNZEO® at page 13. The inactive ingredients
`are butylated hydroxy anisole (BHA), croscarmellose
`sodium, gelatin, glycerin, magnesium stearate, microcrys­
`talline cellulose, mono- and di-glycerides of capryl/capric 15
`acid, polyglyceryl dioleate, povidone K-30, purified water,
`red iron oxide, silicon dioxide, sodium stearyl fumarate,
`sorbitol, sucrose fatty acid esters, titanium dioxide and
`yellow iron oxide. Id.
`10 nous or other parenteral routes, which are safe, therapeuti­
`cally effective, and exhibit prolonged physical and chemical
`stability without any significant loss of potency.
`The recommended dosage of AKYNZEO® capsules in 20
`adults for highly emetogenic chemotherapy (including cis­
`platin-based chemotherapy) is one capsule approximately 1
`hour prior to the start of chemotherapy with 12 mg dexam­
`ethasone administered orally 30 minutes prior to chemo­
`therapy on day 1, and 8 mg of dexamethasone on days 2 to 25
`4. Label for AKYNZEO® at page 3. Further, in case of
`chemotherapy not considered highly emetogenic (including
`anthracyclines and cyclophosphamide-based chemo­
`therapy), the administration of dexamethasone on days 2 to
`4 is not recommended. Id. 30
`It is known in the art that relatively high dose of a drug
`is required for oral dosage forms to achieve similar thera­
`peutic efficacy when compared to injectable dosage forms.
`In addition, nausea and vomiting makes it difficult to admin- 35
`ister oral dosage forms. Hence, there is a need for develop­
`ing stable liquid formulations of netupitant alone or in
`combination with palonosetron, suitable for parenteral
`administration. However, stable liquid formulations contain­
`ing netupitant are difficult to develop and challenging to 40
`manufacture because netupitant is highly insoluble in aque­
`ous environment.
`To overcome these challenges, a prodrug of netupitant,
`i.e., fosnetupitant, has been developed to improve the solu­
`bility of netupitant and obtain a viable stable liquid formu- 45
`lation suitable for parenteral administration. As fosnetupi­
`tant is rapidly converted to netupitant in vivo following IV
`administration, the pharmacology of fosnetupitant is mainly
`attributable to netupitant.
`Injectable formulations comprising a combination of fos- 50
`netupitant and palonosetron are currently approved and
`marketed under the brand name AKYNZEO® in the form of
`lyophilized powder for injection as well as a ready-to-dilute
`solution for injection. Each vial of AKYNZEO® lyophilized
`powder for injection contains 235 mg fosnetupitant and 0.25 55
`mg palonosetron ( equivalent to 0.28 mg palonosetron hydro­
`chloride) and the inactive ingredients are edetate disodium
`(6.4 mg), mannitol (760 mg), sodium hydroxide and/or
`hydrochloric acid (for pH adjustment). Label for
`AKYNZEO® at page 14. Each vial of AKYNZEO® ready- 60
`to-dilute solution for injection contains 235 mg fosnetupi­
`tant and 0.25 mg palonosetron and the inactive ingredients
`are edetate disodium (3.2 mg), mannitol (760 mg), water for
`injection, sodium hydroxide and/or hydrochloric acid (for
`pH adjustment). Id. Both lyophilized powder for injection & 65
`ready-to-dilute solution for injection are indicated in com­
`bination with dexamethasone in adults for the prevention of
`SUMMARY OF THE INVENTION
`In an aspect, the present invention relates to stable liquid
`compositions suitable for parenteral administration compris­
`ing:
`(a) netupitant;
`(b) at least one pharmaceutically acceptable stabilizer;
`( c) at least one pharmaceutically acceptable solubilizer;
`and
`( d) at least one pharmaceutically acceptable vehicle,
`wherein netupitant is present at a concentration of about
`0.5 mg/mL to about 20 mg/mL, and
`wherein the composition is in the form of a solution and
`has a pH of about 2 to about 6.
`In some embodiments, the liquid compositions further
`comprise palonosetron.
`In other embodiments, the compositions further comprise
`one or more pharmaceutically acceptable excipients selected
`from the group consisting of nucleation inhibiting agents,
`tonicity contributing agents, surfactants, buffers, pH adjust­
`ing agents, chelating agents, anti-oxidants, anti-foaming
`agents and preservatives.
`In some embodiments, the solubilizer is selected from
`cyclodextrin, cyclodextrin derivatives, polysorbates, propyl­
`ene glycol, polyethylene glycol or mixtures thereof.
`In some embodiments, the stabilizer is selected from
`tromethamine, phosphoric acid, aspartic acid, tartaric acid,
`citric acid or mixtures thereof.
`In some embodiments, the anti-oxidant is selected from
`sodium ascorbate, ascorbic acid, butylated hydroxytoluene,
`monothioglycerol, sodium thiosulfate, sodium formalde­
`hyde sulfoxylate or mixtures thereof.
`In some embodiments, the vehicle is selected from etha­
`nol, water for injection or mixtures thereof.
`In another aspect, the stable liquid compositions of the
`invention are injectable solutions suitable for subcutaneous,
`intravenous, or intramuscular administration. In certain
`aspects, the inventive compositions are suitable for intrave­
`nous bolus or intravenous infusion administration.
`The solution of the invention may be an aqueous or
`non-aqueous solution.
`In another aspect, the stable solutions of the invention are
`provided as a unit dosage form in a sealed container selected
`from ampoules, vials, and pre-filled syringes.
`In another aspect, the stable solutions are advantageously
`ready-to-use (RTU) or ready-to-dilute (RTD).
`In some embodiments, the stable solution comprises
`palonosetron at a concentration ranging from 0.001 mg/mL
`to about 0.1 mg/mL.
`In some embodiments, the pH of the solution of the
`invention ranges from about 2.5 to about 6.
`In some embodiments, the solution of the invention is
`stable for at least 2 months upon storage at a temperature of
`2-8° C. In some embodiments, the solution of the invention
`Page 3 of 17
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`US 12,097,197 B2
`5
`is stable for at least 2 months upon storage at a temperature
`of 25° C. at 60% relative humidity (25° C./60% RH). In
`some embodiments, the solution of the invention is stable for
`at least 2 months upon storage at a temperature of 40° C. and
`75% relative humidity (40° C./75% RH).
`In an aspect, the stable solution of the invention has a
`level of each known impurity in the solution of less than
`about 0.5% w/w, as measured by HPLC.
`In some embodiments, the stable solution of the invention
`comprises a) netupitant; b) ethanol; c) propylene glycol; d)
`polysorbate 80; e) water, and f) one or more pharmaceuti­
`cally acceptable stabilizers.
`In another embodiment, the stable solution of the inven­
`tion comprises a) netupitant; b) ethanol; c) HP~CD; d)
`polysorbate 80; e) one or more pharmaceutically acceptable
`stabilizers, f) one or more pharmaceutically acceptable anti­
`oxidants and g) water.
`In another embodiment, the stable solution of the inven­
`tion comprises a) netupitant; b) palonosetron hydrochloride;
`c) HP~CD; d) polysorbate 80; e) one or more pharmaceu­
`tically acceptable stabilizers, f) one or more pharmaceuti­
`cally acceptable antioxidants g) ethanol and h) water.
`In another aspect, the present invention provides a stable
`solution suitable for parenteral administration comprising:
`(a) netupitant;
`(b) palonosetron hydrochloride;
`( c) a pharmaceutically acceptable stabilizer;
`( d) a pharmaceutically acceptable solubilizer; and
`6
`solvate, prodrug or hydrate thereof. It also includes geomet­
`ric isomer or a stereoisomer thereof. In some embodiments,
`palonosetron hydrochloride may be used. Any crystalline as
`well as the amorphous form of palonosetron may be used for
`the preparation of compositions of the present invention.
`The terms "about" and "approximate", when used along
`with a numerical variable, generally means the value of the
`variable and all the values of the variable within an experi­
`mental error (e.g., 9 5% confidence interval for the mean) or
`10 within a specified value±10% or within a broader range.
`Within the context of the present invention, the term
`"ready-to-use" or "RTU" as used herein refers to an inject­
`able composition that is stable and is not reconstituted from
`a lyophilizate. The term "ready-to-use" or "RTU" also
`15 encompasses within its scope, injectable compositions that
`does not require any reconstitution or dilution with paren­
`terally acceptable diluent and can be directly administered to
`the patient.
`Within the context of the present invention, the term
`20 "ready-to-dilute" or "RTD" as used herein refers to an
`injectable composition that is diluted with a suitable diluent
`for parenteral administration.
`Within the context of the present invention, the term
`"reference drug product-I" as used herein refers to a ready-
`25 to-dilute injectable product comprising fosnetupitant and
`palonosetron, approved by the U.S. Food and Drug Admin­
`istration (USFDA) under New Drug Application (NDA)
`number 210493 and National Drug Code (NDC) number
`69639-105. ( e) a pharmaceutically acceptable vehicle, wherein the
`solution exhibits bioequivalence to reference drug 30
`product-I or reference drug product-2 (as defined
`herein) upon administration to a subject in need
`thereof.
`Within the context of the present invention, the term
`"reference drug product-2" as used herein refers to a lyo­
`philized injectable product comprising fosnetupitant and
`palonosetron, approved by the U.S. Food and Drug Admin­
`istration (USFDA) under New Drug Application (NDA) In another aspect, the present invention provides a unit
`dosage form comprising the stable solution of the invention
`suitable for parenteral administration comprising (a) 197.5
`mg of netupitant, and (b) 0.28 mg of palonosetron hydro­
`chloride.
`In another aspect, the present invention provides a method
`for prevention of acute and/or delayed nausea and/or vom­
`iting associated with initial and/or repeat courses of cancer
`chemotherapy in a subject in need thereof comprising par­
`enteral administration of a stable solution of the invention
`35 number 210493 and National Drug Code (NDC) number
`69639-102.
`The term "pharmaceutically acceptable liquid vehicle,"
`"pharmaceutically acceptable vehicle," "parenterally
`acceptable liquid vehicle" and "vehicle" are used inter-
`40 changeably.
`comprising (a) a therapeutically effective amount of netu­
`pitant, and (b) a therapeutically effective amount of palo- 45
`nosetron hydrochloride.
`The term "parenteral" or "injectable" refers to routes
`selected from subcutaneous (SC), intravenous (IV), intra­
`muscular (IM), intradermal (ID), intraperitoneal (IP) and the
`like.
`"Bioequivalence" refers to the absence of a significant
`difference between the bioavailability, i.e., the mean ratio of
`AUC ((the area under the curve) over 24 hours) and the
`mean ratio of Cmax (maximum (or peak) serum concentra­
`tion) in blood plasma is within 80% to 125% between two
`DETAILED DESCRIPTION OF THE
`INVENTION
`Unless defined otherwise, all the technical and scientific
`terms used herein have the same meanings as commonly
`known to a person of ordinary skill in the art. In case there
`is a plurality of definitions for the terms used herein, the
`definitions provided herein will prevail.
`As used herein, "a," "an," "the," "at least one," and "one
`or more" are used interchangeably. As used herein, the term
`"or" is generally employed in its usual sense including
`"and/or" unless the content clearly dictates otherwise.
`50 pharmaceutical drug products (e.g., a test composition and a
`reference composition) over the course of a period, at the
`same dose and under the same conditions. The determination
`of whether a test composition is bioequivalent to a reference
`composition is determined by performing a study, referred to
`55 as a bioequivalence or comparative bioavailability study, in
`a group of subjects under controlled conditions.
`The term "subject" refers to an animal, including a human
`or non-human. The terms patient and subject may be used
`interchangeably herein. Non-human animal may be a rat, a
`cat, a dog, a pig, a rabbit, a mouse, or a guinea pig.
`The term "Cmax" as used herein, refers to a maximum
`concentration of a drug in blood, serum, a specified com­
`partment, or test area of a subject between administration of
`a first dose and administration of a second dose. The term
`As used herein the term "netupitant" refers to netupitant 60
`free base or a pharmaceutically acceptable salt, solvate or
`hydrate thereof. It also includes geometric isomer or a
`stereoisomer thereof. Any crystalline as well as the amor­
`phous form of netupitant may be used for the preparation of
`compositions of the present invention. 65 Cmax could also refer to dose normalized ratios if specified.
`As used herein, the term "palonosetron" refers to palo­
`nosetron free base or a pharmaceutically acceptable salt,
`As used herein, "C 12/' refers to the plasma concentration
`measured at 12 hours from administration.
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`US 12,097,197 B2
`7
`The term "T max," as used herein, refers to a time or period
`after administration of a drug when the maximum concen­
`tration (Cmax) is reached in blood, serum, a specified com­
`partment, or test area of a subject. As used herein, "T 1/2"
`refers to the time at which the plasma concentration is half
`of the observed maximum.
`The term "AUC 0 _=", means the area under a plasma drug
`concentration-time curve from time point of 0 to infinity
`after drug administration.
`The term "AUC 0 _," means the area under a plasma drug
`concentration-time curve from time points of O to t after
`drug administration, wherein t is time in hours and is in
`between 1 hour to 72 hours.
`As used herein, the term "storage" refers to the holding of
`a composition under controlled or uncontrolled conditions
`for a period ranging from a few minutes to several months
`or longer. Storage conditions that can be controlled include,
`for example, temperature, humidity, and the level oflight. In
`many cases, storage of a pharmaceutical formulation is
`under industry acceptable standards and/or standards that are
`mandated by regulatory agencies, such as USFDA.
`The objective of the present invention is to increase the
`solubility of netupitant enabling formulation of netupitant
`solution product. Another objective of the present invention
`is to provide stable aqueous solutions of netupitant and
`palonosetron having long-term storage stability.
`The inventive pharmaceutical compositions described
`herein may be provided in the form of a solution suitable for
`injection. To prepare such composition, active drug is dis­
`solved in a parenterally acceptable liquid vehicle.
`The pharmaceutically acceptable liquid vehicles may be
`any combination of pharmaceutically acceptable liquids
`suitable for parenteral administration. Suitable vehicles
`include ethanol, liquid polyethylene glycol, and propylene
`glycol, water, water for injection, isotonic sodium chloride
`solution, fixed oils, such as corn oil, cottonseed oil, peanut
`oil, and sesame oil, and suitable mixtures thereof.
`As used herein, when pH of the composition is referred to
`in the context of a non-aqueous vehicle for the liquid
`compositions of the invention, the pH value refers to the
`measurement obtained when a simple extraction procedure
`using water is used for measuring the pH of the non-aqueous
`solution. Water is added and mixed thoroughly with the
`sample. After reaching equilibrium, the solvent phase is
`separated, if immiscible, and the pH of the water phase is
`then measured.
`In some embodiments, the vehicle is selected from the
`group consisting of ethanol, water, water for injection,
`isotonic sodium chloride solution, or suitable mixtures
`thereof.
`In an embodiment of the invention, the ready-to-use or
`ready-to-dilute compositions may be formulated as aqueous
`or non-aqueous solutions. Preferably, the ready-to-use or
`ready-to-dilute compositions will include a vehicle in an
`amount from about 5 mL to greater than or equal to 250 mL.
`According to the present invention, the ready-to-dilute
`compositions may be provided in a kit form along with
`parenterally acceptable diluent. Parenterally acceptable
`diluents include water for injection, 0.9% saline (normal
`saline), 0.45% saline (half normal saline), 2.5% dextrose/
`0.45% saline, 5% dextrose solution, ringer's solution, and
`ringer's lactate solution.
`In certain non-limiting embodiments, netupitant is formu­
`lated as a composition, wherein netupitant is the only
`therapeutically active ingredient present in the composition.
`In another non-limiting embodiment, netupitant is combined
`with palonosetron and formulated as a composition. In yet
`8
`another non-limiting embodiment, netupitant is combined
`with palonosetron and dexamethasone and formulated as a
`composition.
`In some embodiments, netupitant is present at a concen­
`tration of about 0.5 mg/mL or more. In some embodiments,
`stable ready-to-use or ready-to-dilute solutions of the pres­
`ent invention comprise netupitant, wherein netupitant is
`present at a concentration about 0.5 mg/mL, about 0.987
`mg/mL, about 1.975 mg/mL, about 3.95 mg/mL, about
`10 13.13 mg/mL, or about 15.2 mg/mL.
`The stable ready-to-use or ready-to-dilute solutions of the
`present invention may comprise netupitant at a concentra­
`tion ranging from about 0.5 mg/mL to about 30 mg/mL, or
`from about 0.5 mg/mL to about 25 mg/mL. In some embodi-
`15 ments, stable ready-to-use solutions of the present invention
`comprise netupitant at a concentration ranging from about
`0.5 mg/mL to about 5 mg/mL. In some embodiments, stable
`ready-to-dilute solutions of the present invention comprise
`netupitant at a concentration ranging from about 10 mg/mL
`20 to about 1 7 mg/mL.
`The present invention further relates to injectable solu­
`tions of netupitant and palonosetron, wherein palonosetron
`is present at a concentration of about 0.001 mg/mL or more.
`For example, palonosetron hydrochloride is may be present
`25 at a concentration of about 0.0014 mg/mL, about 0.0028
`mg/mL, about 0.0056 mg/mL, about 0.0186 mg/mL, or
`about 0.0215 mg/mL.
`In certain embodiments of the present invention, solubil­
`ity of netupitant is increased by one or more of the methods
`30 selected from a) particle size reduction, b) solid dispersion,
`c) complexation, d) high-speed stirring, e) in situ salt
`formation, and/or f) use of solubilizing agents.
`The solubilizer is any suitable compound that increases
`the solubility of netupitant in the chosen pharmaceutical
`35 acceptable vehicle. In some embodiments, the liquid com­
`position comprises at least one solubilizer selected from
`cyclodextrin, cyclodextrin derivatives, polysorbates, propyl­
`ene glycol, and polyethylene glycol or mixtures thereof. The
`amount of solubilizer may range from about 0.1 mg/mL to
`40 about 200 mg/mL of the composition, and preferably from
`about 0.5 mg/mL to about 100 mg/mL.
`Cyclodextrins used in the present invention include a-cy­
`clodextrin, substituted or non-substituted ~-cyclodextrin,
`1\-cyclodextrin, y-cyclodextrin, or combinations thereof.
`45 Examples of substituted ~-cyclodextrins include those sub­
`stituted with one or more hydrophilic groups, such as
`monosaccharide ( e.g., glucosyl, maltosyl), carboxyalkyl
`(e.g., carboxyl methyl, carboxyethyl), hydroxyalkyl-substi­
`tuted (e.g., hydroxyethyl, 2-hydroxypropyl) and sulfoalky-
`50 lether-substituted-~-cyclodextrin.
`In some embodiments, the cyclodextrin is a substituted
`~-cyclodextrin, particularly, hydroxypropyl-~-cyclodextrin
`(HP-~-CD) and sulfobutylether-~-cyclodextrin (SBE-~­
`CD). However, it is understood that typically any substitu-
`55 tion to the cyclodextrin, including substitution by hydro­
`phobic groups such as hydroxyalkyl-substituted­
`cyclodextrin, will improve its aqueous solubility by
`disrupting the hydrogen-bonding network within the crystal
`lattice of the solid cyclodextrin, thereby lowering the lattice
`60 energy of the solid. The degree of substitution is not believed
`to be critical; however, the degree of substitution is advan­
`tageously at least 1 % and typically 2% to 10%, such as 3%
`to 6%.
`Particularly suitable ~-cyclodextrins include for example
`65 but not limited to, Cavasol® W7 HP (hydroxypropyl-~­
`cyclodextrin (HP-~-CD), Kleptose® HP (hydroxypropyl-~­
`cyclodextrin (HP-~-CD)), Cavamax® W7 (~-cyclodextrin),
`Page 5 of 17
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`US 12,097,197 B2
`9
`Captisol® (sulfoalkyl ether-~-cyclodextrin), Cavasol® W7
`M (methyl-~-cyclodextrin), Cavasol® W8 HP (hydroxypro­
`pyl-y-cyclodextrin), Cavamax® W8 (y-cyclodextrin),
`Cavamax® W6 (a-cyclodextrin).
`In one embodiment, the cyclodextrin is 2-hydroxypropyl­
`~-cyclodextrin (HP-~-CD), which is a cyclic oligosaccha­
`ride containing seven D-( + )-glucopyranose units.
`Stabilizers increase stability of netupitant in the chosen
`pharmaceutical acceptable vehicle. The stabilizer may be
`selected from, but are not limited to, inorganic acids such as 10
`hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
`acid, phosphoric acid and the like, and organic acids such as
`adipic acid, acetic acid, ascorbic acid, aspartic acid, benzoic
`acid, cinnamic acid, glutamic acid, glycolic acid, citric acid,
`succinic acid, tartaric acid, lactic acid, fumaric acid, maleic 15
`acid, malic acid, malonic acid, mandelic acid, methane
`sulfonic acid, ethane sulfonic acid, propionic acid, pyruvic
`acid, toluene sulfonic acid, salicylic acid and oxalic acid and
`combinations thereof. The amount of stabilizer may range
`from about 0.1 mg/mL to about 250 mg/mL of the compo- 20
`sition, and preferably from about 0.5 mg/mL to about 200
`mg/mL.
`In some embodiments of the present invention, pharma­
`ceutical compositions may contain buffering agents, which
`are used to resist change in pH upon dilution or addition of 25
`acid or alkali. Such compounds include, by way of example
`and without limitation, sodium dihydrogen phosphate mono­
`hydrate, disodium hydrogen phosphate anhydrous, benzoic
`acid, sodium benzoate, monobasic sodium phosphate, diba-
`sic sodium phosphate, disodium hydrogen phosphate 30
`dodecahydrate, tromethamine (TRIS buffer), potassium
`metaphosphate, potassium phosphate, monobasic sodium
`acetate, sodium bicarbonate, sodium carbonate, potassium
`carbonate, sodium tartrate and others known to those of
`ordinary skill in the art. The amount of buffering agent may 35
`range from about 0.1 mg/mL to about 50 mg/mL of the
`composition, and preferably from about 0.5 mg/mL to about
`25 mg/mL.
`10
`In some embodiments of the present invention, a stable
`solution suitable for parenteral administration comprises: (a)
`netupitant (b) palonosetron hydrochloride, ( c) stabilizer, ( d)
`solubilizer, and ( e) a vehicle, wherein said solution does not
`contain chelating agent.
`In some embodiments of the present invention, pharma­
`ceutical compositions may contain an antioxidant which
`inhibits oxidation and thus is used to prevent the deteriora­
`tion of preparations by the oxidative process. Such com­
`pounds include by way of example and without limitation
`sodium bisulfate, sodium ascorbate, ascorbic acid, ascorbyl
`palmitate, glycine, L-cysteine hydrochloride, L-methionine,
`butylated hydroxy anisole, butylated hydroxytoluene, hydro
`phosphorous