Compositions and methods for treating centrally mediated nausea and vomiting

Abstract

Provided are compositions and methods for treating or preventing nausea and vomiting in patients undergoing chemotherapy, radiotherapy, or surgery.

Claims

1. A method of treating emesis in a patient in need thereof comprising orally administering to said patient a solid oral dosage form comprising a combination of a therapeutically effective amount of palonosetron or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of netupitant or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein said emesis is induced by cancer chemotherapy or radiotherapy.

3. The method of claim 1, wherein the emesis is induced by highly emetogenic or moderately emetogenic chemotherapy.

4. The method of claim 1, wherein said treating comprises preventing said emesis.

5. The method of claim 1, further comprising administering chemotherapy to said patient after said solid oral dosage form, wherein said solid oral dosage form is administered no more than two hours before said chemotherapy.

6. The method of claim 1, wherein said therapeutically effective amounts comprise from 100 to 300 mg of netupitant and 0.5 mg of palonosetron hydrochloride based on the weight of the free base.

7. The method of claim 1, wherein said therapeutically effective amounts comprise 300 mg of netupitant and 0.5 mg of palonosetron hydrochloride based on the weight of the free base.

8. A method of treating delayed-onset emesis in a patient in need thereof comprising orally administering to said patient a solid oral dosage form comprising a combination of a therapeutically effective amount of palonosetron or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of netupitant or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein said emesis is induced by cancer chemotherapy or radiotherapy.

10. The method of claim 8, wherein the emesis is induced by highly emetogenic or moderately emetogenic chemotherapy.

11. The method of claim 8, wherein said treating comprises preventing said emesis.

12. The method of claim 8, further comprising administering chemotherapy to said patient after said solid oral dosage form, wherein said solid oral dosage form is administered no more than two hours before said chemotherapy.

13. The method of claim 8, wherein said therapeutically effective amounts comprise from 100 to 300 mg of netupitant and 0.5 mg of palonosetron hydrochloride based on the weight of the free base.

14. The method of claim 8, wherein said therapeutically effective amounts comprise 300 mg of netupitant and 0.5 mg of palonosetron hydrochloride based on the weight of the free base.

15. An orally administered dosage form comprising a combination of a therapeutically effective amount of palonosetron or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of netupitant or a pharmaceutically acceptable salt thereof.

16. The dosage form of claim 15, wherein said therapeutically effective amounts are effective to treat emesis induced by cancer chemotherapy or radiotherapy.

17. The dosage form of claim 15, wherein said therapeutically effective amounts comprise from 100 to 300 mg of netupitant and 0.5 mg of palonosetron hydrochloride based on the weight of the free base.

18. The dosage form of claim 15, wherein said therapeutically effective amounts comprise 300 mg of netupitant and 0.5 mg of palonosetron hydrochloride based on the weight of the free base.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

(2) FIG. 1 depicts a capsule containing one soft-gel capsule of palonosetron and three tablets of netupitant.

(3) FIG. 2 is a two dimensional graph plotting the pharmacokinetic profile of netupitant in humans following oral administration of netupitant alone and netupitant together with palonosetron.

(4) FIG. 3 is a two dimensional graph plotting the pharmacokinetic profile of palonosetron in humans following oral administration of palonosetron alone and palonosetron together with netupitant.

(5) FIG. 4 is a two dimensional graph plotting mean plasma concentrations of dexamethasone over time following administration with and without netupitant.

(6) FIG. 5 contains two bar graphs that depict the average NK.sub.1 receptor occupancy at 6, 24, 48, 72 and 96 hours after a single oral dose of 100, 300 and 450 mg. netupitant (N=2 for each dose) in striatum and occipital cortex, as measured using positron emission topography.

DETAILED DESCRIPTION OF THE INVENTION

(7) The present invention may be understood more readily by reference to the following definitions and detailed description of preferred embodiments of the invention and the non-limiting Examples included therein.

(8) Definitions and Use of Terms

(9) When the singular forms “a,” “an” and “the” or like terms are used herein, they will be understood to include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like. The word “or” or like terms as used herein means any one member of a particular list and also includes any combination of members of that list.

(10) When used herein the term “about” or “ca.” will compensate for variability allowed for in the pharmaceutical industry and inherent in pharmaceutical products, such as differences in product strength and bioavailability due to manufacturing variations and time-induced product degradation. The term allows for any variation which in the practice of pharmaceuticals would allow the product being evaluated to be considered pharmaceutically equivalent or bioequivalent, or both if the context requires, to the recited strength of a claimed product.

(11) Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps.

(12) As used herein, the term “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use. In addition, the term “pharmaceutically acceptable salt” refers to a salt of a compound to be administered prepared from pharmaceutically acceptable non-toxic acids. Examples of suitable inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric. Suitable organic acids may be selected from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like.

(13) Pharmaceutically acceptable salts of palonosetron include palonosetron hydrochloride. Pharmaceutically acceptable pro-drugs of netupitant include those described in U.S. Pat. Nos. 6,593,472, 6,747,026 and 6,806,370, including the N-oxide of netupitant. The contents of these publications are incorporated herein by reference. When a molecule is referred to herein in its base or salt form, it will be understand also to encompass other pharmaceutically acceptable salt forms of the molecule.

(14) As used herein, “therapeutically effective amount” refers to an amount sufficient to elicit the desired biological response. The therapeutically effective amount or dose will depend on the age, sex and weight of the patient, and the current medical condition of the patient. The skilled artisan will be able to determine appropriate dosages depending on these and other factors in addition to the present disclosure.

(15) The minimum effective dose of dexamethasone, when used to treat CINV induced by highly emetogenic chemotherapy, has been demonstrated to be 20 mg. administered orally or by injection on day one, and sixteen mg. administered orally or by injection on days two, three and four. Jordan et al., THE ONCOLOGIST, Vol. 12, No. 9, 1143-1150, September 2007. When used to treat CINV induced by moderately emetogenic chemotherapy, the minimum effective dose of dexamethasone is 20 mg. administered orally or by injection on day one, and zero mg. on days two, three and four.

(16) The terms “treating” and “treatment,” when used herein, refer to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

(17) As used herein, the term “significantly” refers to a level of statistical significance. The level of statistical significant can be, for example, of at least p<0.05, of at least p<0.01, of at least p<0.005, or of at least p<0.001. Unless otherwise specified, the level of statistical significance is p<0.05. When a measurable result or effect is expressed or identified herein, it will be understood that the result or effect is evaluated based upon its statistical significance relative to a baseline. In like manner, when a treatment is described herein, it will be understood that the treatment shows efficacy to a degree of statistical significance.

(18) 5-HT.sub.3 antagonists include the various setrons such as, for example, palonosetron, ondansetron, dolasetron, tropisetron, and granisetron, and their pharmaceutically acceptable salts. A preferred 5-HT.sub.3 antagonist is palonosetron, especially its hydrochloride salt.

(19) “Highly emetogenic chemotherapy” refers to chemotherapy having a high degree of emetogenic potential, and includes chemotherapy based on carmustine, cisplatin, cyclophosphamide >1500 mg/m.sup.2, dacarbazine, dactinomycin, mechlorethamine, and streptozotocin.

(20) “Moderately emetogenic chemotherapy” refers to chemotherapy having a moderate degree of emetogenic potential, and includes chemotherapy based on carboplatin, cyclophosphamide <1500 mg/m.sup.2, cytarabine >1 mg/m.sup.2, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, and oxaliplatin.

(21) Acute emesis refers to the first twenty-four hour period following an emesis-inducing event. Delayed emesis refers to the second, third, fourth and fifth twenty-four hour periods following an emesis-inducing event. When a treatment is said to be effective during the delayed phase, it will be understood to mean that the effectiveness of the treatment is statistically significant during the entire delayed phase, regardless of whether the treatment is effective during any particular twenty-four hour period of the delayed phase. It will also be understood that the method can be defined based upon its effectiveness during any one of the twenty-four hour periods of the delayed phase. Thus, unless otherwise specified, any of the methods of treating nausea and/or vomiting during the delayed phases, as described herein, could also be practiced to treat nausea and/or vomiting during the second, third, fourth or fifth twenty-four hour periods following an emesis inducing event, or an combination thereof.

(22) When ranges are given by specifying the lower end of a range separately from the upper end of the range, it will be understood that the range can be defined by selectively combining any one of the lower end variables with any one of the upper end variables that is mathematically possible.

(23) Methods of Treatment

(24) As noted above, the invention is premised on several unique discoveries, and provides the following independent methods that can be practiced according to the present invention, including:

(25) In a first principal embodiment, the invention provides a method of treating nausea and vomiting for a period of five consecutive days in a patient in need thereof, comprising administering to said patient netupitant or a pharmaceutically acceptable salt thereof in an amount which is therapeutically effective to treat nausea and vomiting during the acute and delayed phases, which enters the systemic circulation, crosses the blood brain barrier and occupies at least 70% of NK.sub.1 receptors in the striatum seventy-two hours after said administration.

(26) In a second principal embodiment, the invention provides a combination therapy for treating nausea and vomiting for five consecutive days in a patient in need thereof, comprising: (i) administering to said patient on day one netupitant or a pharmaceutically acceptable salt thereof, in an amount which is therapeutically effective to treat nausea and vomiting during the acute and delayed phases, which enters the systemic circulation, crosses the blood brain barrier and occupies at least 70% of NK.sub.1 receptors in the striatum seventy-two hours after said administration; (ii) administering to said patient on day one a therapeutically effective amount of a 5-HT.sub.3 antagonist (preferably palonosetron, more preferably 0.5 mg. of oral palonosetron as palonosetron hydrochloride) effective to treat said nausea and vomiting during the acute and delayed phases; (iii) administering to said patient on day one a first dose of dexamethasone which is ineffective against nausea and vomiting when administered alone, but effective against nausea and vomiting when administered in combination with said netupitant and palonosetron, wherein said first dose comprises from 50 to 70% of a minimum effective dose when administered alone; and (iv) if the patient is undergoing highly emetogenic chemotherapy, administering to said patient, on days two, three and four, a second dose of dexamethasone which is ineffective against nausea and vomiting when administered alone, but effective against nausea and vomiting when administered in combination with said netupitant, wherein said second dose comprises from 40 to 60% of a minimum effective dose when administered alone on days two, three and four.

(27) Various sub-embodiments are envisaged for these principal embodiments. For example, the netupitant can be administered as a free base or a pharmaceutically acceptable salt thereof, but is preferably administered as the free base. In addition, the netupitant is preferably administered in an amount ranging from about 50 to about 500 mg., from about 200 to about 400 mg., and preferably about 300 mg., based on the weight of the free base. A preferred route of administration for the netupitant is oral. In terms of binding to NK.sub.1 receptors, the netupitant preferably binds to at least 80 or even 85% of NK.sub.1 receptors in the striatum seventy-two hours after administration. As of ninety six hours after administration, the netupitant preferably binds less than 70, 60, 50 or even 40% of said NK.sub.1 receptors.

(28) The methods of the present invention are all effective at treating or preventing nausea and vomiting induced by numerous events, including chemotherapy induced nausea and vomiting (“CINV”), from moderately or highly emetogenic chemotherapy, radiation therapy induced nausea and vomiting (“RINV”), and post-operative nausea and vomiting (“PONV”). The method is preferably performed shortly before the emesis inducing event (i.e. no more than 1 or 2 hours before the event). The methods may be used to treat nausea and vomiting during the acute phase of emesis, or during the delayed phase.

(29) The drugs specified by the individual embodiments may be administered by any suitable dosing regimen, as is well known in the art, but in a preferred embodiment the netupitant, 5-HT.sub.3 antagonist and steroid are administered orally. A preferred oral dose of palonosetron ranges from about 0.075 to about 1.0 mg, or from about 0.25 to about 0.75 mg, but is preferably about 0.5 mg. A preferred oral dose of netupitant ranges from about 50 to 500 mg, or from about 200 to about 400 mg, but is preferably about 300 mg. A preferred dose of corticosteroid, preferably dexamethasone, is 12 mg administered orally or via injection on the first day of treatment, and 8 mg administered orally or via injection on the second, third and fourth days after said treatment.

(30) It will be further understood that the netupitant can be administered in prodrug form, in which case the invention will provide a method of treatment by inducing plasma levels of netupitant, and in each case the plasma level of netupitant induced by the prodrug administration will correspond to the level attained by the administration of netupitant or its pharmaceutically acceptable salt, in the doses and routes of administration described herein.

(31) Pharmaceutical Compositions

(32) Various pharmaceutical compositions can be developed that make use of the combinations described herein. The composition can be administered by any appropriate route, for example, orally, parenterally, or intravenously, in liquid or solid form.

(33) Preferred modes of administrations of the active compounds are injectable and/or oral. These compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules (for oral use) or compressed into tablets (for oral or buccal use) or formulated into troches (for buccal use). For these purposes, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.

(34) Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a gliding such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.

(35) The compounds can be administered as a component of an elixir, suspension, syrup, wafer, orally disintegrating film, orally disintegrating tablet, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

(36) Solutions or suspensions used for injection can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride, mannitol and dextrose. An injectable preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

(37) Combined Oral Dosage Forms

(38) As discussed above, the invention provides versatile combined oral dosage forms of palonosetron and an NK1 antagonist that can be readily modified depending on the therapeutic objective, and that do not present issues of stability and degradation. In a preferred embodiment, the invention provides a capsule for oral administration made from a hard outer shell that houses one or more NK1 antagonist tablets and one or more palonosetron soft-gel capsules. The finished capsule and the tablet(s) and soft-gel capsule(s) housed within the capsule shell are all preferably formulated as immediate release dosage forms. Netupitant and casopitant, and their pharmaceutically acceptable salts, are particularly preferred NK.sub.1 antagonists for the combined oral dosage forms of this invention.

(39) While the NK1 antagonist is preferably formulated in a solid tablet, it will be understood that it can be formulated in any solid form that is suitable for oral administration including, for example, a tablet or capsule (hard or soft-gel). In a preferred embodiment, the NK1 antagonist is formulated in a tablet. The number of NK1 antagonist units contained within the combined dosage form can be, for example, from 1 to 10, 1 to 5, or 1 to 3. The netupitant units within the combined dosage form can provide anywhere from 50 to 500 mg of netupitant on an aggregate basis, preferably from 100 to 350 mg. Each netupitant unit preferably comprises from 50 to 200 mg of netupitant, more preferably 100 to 150 mg of netupitant, and most preferably 100 or 150 mg of netupitant.

(40) The palonosetron can also be formulated in any solid form that is suitable for oral administration, although it is preferably formulated as a soft-gel capsule. Non-limiting examples of suitable palonosetron soft-gel capsules are provided in PCT publication WO 2008/049552, the contents of which are hereby incorporated by reference. The number of palonosetron units within the combined dosage from can be, for example, from 1 to 5, from 1 to 3 or just 1. Each of the palonosetron units within the combined dosage form can provide anywhere from 0.01 to 5.0 mg palonosetron, preferably from 0.1 to 1.0 mg palonosetron on an aggregate basis. Each palonosetron unit will preferably comprise from 0.1 to 1.0 mg of palonosetron, most preferably about 0.25, 0.5, 0.75 or 1.0 mg of palonosetron.

(41) FIG. 1 illustrates an exemplary embodiment of a combined oral dosage form of palonosetron and netupitant. The dosage form 10 comprises a two piece hard outer shell that includes a body 20 and a cap 22. The dosage form 10 contains one palonosetron soft-gel capsule 30 (preferably containing 0.5 mg of palonosetron) and three netupitant tablets 40 (each preferably containing 100 mg of netupitant).

(42) Hard Outer Shell

(43) The hard outer shell of the present invention can be made of any pharmaceutically acceptable material that dissolves in gastric fluids. Preferred materials for the hard outer shell include, for example, gelatin, cellulose, starch, or hydroxypropyl methylcellulose (HPMC). In a particular embodiment of the invention, the hard outer shell has a maximum oxygen permeability. Preferably, the oxygen permeability is less about 1.0×10.sup.−3, 5.0×10.sup.−4, 1.0×10.sup.−4, 5.0×10.sup.−5, or even 2.0×10.sup.−5 ml.Math.cm/(cm.sup.2.Math.24 hr. atm).

(44) The hard outer shell can be a continuous structure. Alternatively, the hard outer shell can be a two-piece hard capsule.

(45) Soft-Gel Capsule

(46) The soft-gel capsule used for the palonosetron preferably comprises a soft outer shell and a liquid inner fill composition comprising palonosetron hydrochloride. Non-limiting examples of suitable palonosetron soft-gel capsules are provided in PCT publication WO 2008/049552, the contents of which are hereby incorporated by reference.

(47) The soft outer shell of the soft-gel capsule can contain any type of material that dissolves in gastric fluids. Preferred materials for the soft outer shell include, for example, gelatin, cellulose, starch, or hydroxypropyl methylcellulose (HPMC). The soft-gel capsule can further comprise shell excipients such as glycerin, sorbitol, and colorants/opacifers such as titanium dioxide. The soft-gel capsule can further include solvents such as purified water. In particular embodiments of the invention, the outer shell has a maximum oxygen permeability, preferably of no more than 1.0×10.sup.−3, 5.0×10.sup.−4, 1.0×10.sup.−4, 5.0×10.sup.−5, or even 2.0×10.sup.−5 ml.Math.cm/(cm.sup.2.Math.24 hr. atm). Suitable soft-gel capsules include the 1.5-oval gelatine capsule shell manufactured by Catalent Pharma Solutions.

(48) The liquid fill is preferably composed predominantly of one or more lipophilic components in an amount of from 50 wt. % to 99 wt. %, preferably from 75 wt. % to 98 wt. %. Preferred lipophilic components include, for example, mono- and di-glycerides of fatty acids, especially including the mono- and di-glycerides of capryl/capric acid. The liquid fill may also contain glycerin, preferably in an amount of from 1 to 15 wt. %, more preferably from 2 to 10 wt. %. In one preferred embodiment, both the shell and the inner fill composition comprise glycerin. In another preferred embodiment, the liquid fill comprises about 0.25, 0.50, 0.75 mg., or more of palonosetron as palonosetron hydrochloride.

(49) The fill composition may comprise various means to facilitate the transition of palonosetron from the dosage form to the gastrointestinal fluids of the GI tract, so that the palonosetron may be more readily absorbed into the bloodstream. For example, the liquid fill composition may contain a surfactant, optimally in an amount of from 0.1 wt. % to 6 wt. %, from 0.5 wt. % to 5 wt. %, or from 1.0 wt. % to 3.0 wt. %. The liquid fill composition preferably comprises greater than 0.1, 0.5, or 1.0 wt. % of surfactant, and less than 10, 8, 5, 4, or even 4 wt. % of surfactant. A particularly preferred surfactant is polyglyceryl oleate.

(50) Alternatively or in addition, the transitioning means for a liquid filled capsule may comprise water that forms a single phase or microemulsion with the other liquid ingredients in the excipient base. The liquid fill composition preferably comprises from 0.05 wt. % to 30 wt. % water, from 1 wt. % to 20 wt. % water, or from 2 wt. % to10 wt. % water. The liquid fill preferably comprises greater than 0.1, 0.5 or 1.0 wt. % water, and less than 20, 15, 10, 8 or 5 wt. % water.

(51) The active agent, which is preferably palonosetron hydrochloride, is preferably present in the fill composition in an amount ranging from 0.01 to 10.0 wt. %, from 0.05 to 5.0 wt. %, or from 0.1 wt. % to 2.0 wt. %. Alternatively, particularly stable formulations have been found where the concentration of palonosetron exceeds 0.3%, preferably at a concentration no greater than 1 wt. %.

(52) Tablet

(53) The tablets of the present invention can include from 20 to 95 wt. % of NK1 antagonist (preferably netupitant), and preferably comprises from 60 to 80 wt. % of netupitant. In addition, the tablets can contain diluents, disintegrants, surfactants, binders, glidants, and/or lubricants. In a particular embodiment, the tablet comprises from 5 to 25 wt. % of microcrystalline cellulose. The microcrystalline cellulose can function as a diluent and disintegrant, and preferably comprises 15 wt. % of the tablet. Another suitable disintegrant is sodium croscaramellose, which can be present in the tablet in an amount of from 1 to 5 wt. %, preferably 2 wt. %.

(54) A suitable binder for use in the tablet is polyvinylpyrrolidone, which can be present in the tablet in an amount from 1 to 10 wt. % of the tablet, and preferably 5 wt. %. A suitable glidant for use in the tablet is colloidal silicon dioxide, which can be present in the tablet in an amount of 2 wt. %. Suitable lubricants for use in the tablet include sodium stearyl fumarate and magnesium stearate, which can be present in the tablet in an amount of 0.7 wt. % and 0.35 wt. %, respectively.

(55) Application of The Combined Oral Dosage Forms

(56) The invention further provides a method of treating emesis comprising orally administering to a patient suffering from emesis, or at risk for suffering emesis, a dosage form of the present invention. In still further embodiments, the invention provides methods of treating emesis by administering one or more of the dosage forms described herein. The dosage form is preferably administered shortly before the emesis inducing event (i.e. no more than 2 hours before the event). The emesis may be acute phase emesis (i.e. emesis experienced within about 24 hours of an emesis inducing event), or delayed emesis (i.e. emesis experienced after the acute phase, but within seven, six, five or four days of an emesis inducing event). The emesis may constitute chemotherapy induced nausea and vomiting (“CINV”), from moderately or highly emetogenic chemotherapy, radiation therapy induced nausea and vomiting (“RINV”), or postoperative nausea and vomiting (“PONV”).

EXAMPLES

(57) The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C. or is at room temperature, and pressure is at or near atmospheric.

Example 1: Preparation of Oral Dosage Form

(58) In a preferred embodiment the combination is administered in a capsule oral dosage form, wherein the capsule houses one or more soft-gel capsules for the palonosetron and one or more hard tablets for the netupitant. Table 1 below describes a representative formulation for a soft-gel capsule containing 0.5 mg of palonosetron, suitable for inclusion in such a hard outer shell.

(59) TABLE-US-00001 TABLE 1 REPRESENTATIVE SOFT-GEL FORMULATION Approximate Amount Ingredient (mg/Capsule) Function Fill Solution Palonosetron HCl 0.56.sup.1 Active Mono-and di-glycerides of Capryl/Capric 62.19 Solvent vehicle Acid (Capmul MCM) Glycerin, anhydrous, USP/Ph Eur 3.37 Plasticizer Polyglyceryl oleate (Plurol Oleinue CC 497) 0.87 Surfactant Purified water, USP/Ph Eur 2.94 Co-solvent Butylated hydroxyanisole (BHA), NF/Ph Eur 0.07 Antioxidant Nitrogen — Theoretical fill weight 70.00 mg Gelatine Capsule Shell, 1.5-oval (Catalent Pharma Solutions).sup.2 Gelatine (type 195), NF/Ph Eur — Shell Sorbitol Special/Glycerin Blend 50/50 — Plasticizer Titanium dioxide, USP/Ph Eur — Colorant/Opacifier Purified water, USP/Ph Eur — Solvent .sup.1Corresponds to 0.50 mg. free base .sup.2Quantitative composition of capsule shell is proprietary to Catalent Pharma Solutions

(60) Table 2 below describes a representative formulation for a tablet containing 100 mg. of netupitant, suitable for inclusion in a hard shell.

(61) TABLE-US-00002 TABLE 2 REPRESENTATIVE TABLET FORMULATION Approximate Amount Ingredient (mg/Tablet) Function Netupitant, milled 100 Active Microcrystalline cellulose pH 101 20.5 Diluent and disintegrant Sucrose Lauric Acid Esters 10.0 Surfactant Polyvinilpyrrolidone K30 7.0 Binder Sodium croscaramellose 3.0 Disintegrant Colloidal Silicon Dioxide 3.0 Glidant Sodium Stearyl Fumarate 1.0 Lubricant Magnesium Stearate 0.5 Lubricant Total weight 145 mg

Example 2: Pharmacokinetics of Combined Dosage Form

(62) Objective

(63) The effects of palonosetron on the pharmacokinetics (PK) of netupitant and the effects of netupitant on the PK of palonosetron were examined in healthy volunteers.

(64) Methods

(65) A randomized, open, 3-way crossover study was conducted. Each subject participated in 3 treatment periods, each lasting approximately 12 days (Day -1 to Day 11). The treatment periods were separated by wash-out periods of no less than 14 days (between Day 1 of any 2 consecutive treatment periods).

(66) The following treatments were investigated:

(67) Treatment A: oral netupitant 450 mg. administered as single dose of three 150 mg. capsules.

(68) Treatment B: oral palonosetron 0.75 mg. and oral netupitant 450 mg. administered simultaneously as three capsules of 150 mg. netupitant followed by 1 capsule of 0.75 mg. palonosetron.

(69) Treatment C: oral palonosetron 0.75 mg. administered as single dose as one 0.75 mg. capsule.

(70) Doses were administered under fasting conditions. Subjects fasted over-night for approximately 10 hours. Water, however, was permitted up to 1 hour pre-dose. Food intake was permitted 4 hours post-dose, and water was allowed ad libitum 1 hour post-dose.

(71) Doses were administered with the subject in an upright position. The subjects remained in an upright position for 4 hours post-dose. The capsules were swallowed whole with 250 mL of room-temperature tap water. Repeated PK blood sampling (for netupitant and/or palonosetron) was performed.

(72) Results

(73) The primary PK variables assessed for netupitant and palonosetron were the maximum plasma concentration observed (C.sub.max), the area under the plasma concentration versus time curve from time zero to the last quantifiable sampling time point (t) (AUC.sub.0-t), and the area under the plasma concentration versus time curve from time zero to infinity (AUC.sub.0-inf). The secondary PK variables assessed were the terminal elimination half-life (t.sub.1/2,z), and the time at which the maximum plasma concentration was observed (t.sub.max). Results are depicted in below Tables 3 and 4, as well as FIGS. 2 and 3.

(74) TABLE-US-00003 TABLE 3 Summary of Netupitant Pharmacokinetic Parameters Palonosetron 0.75 mg + Parameter Netupitant 450 mg Netupitant 450 mg AUC.sub.0-t [h*μg/L] 22808 (7270) 22775 (10064) AUC.sub.0-inf [h*μg/L] 25927 (10156) 26241 (13219) C.sub.max [μg/L] 650.2 (257.8) 659.7 (325.7) t.sub.max (h) 4.50 (3.00; 24.00) 4.50 (3.00; 23.95) t.sub.1/2.z (h) 71.81 (37.10; 261.61) 78.31 (50.17; 196.13) Mean and SD are shown, except for t.sub.max and t.sub.1/2, where median and range are shown.

(75) As can be seen in Table 4 below, palonosetron shows a better pharmacokinetic profile when combined with Netupitant as opposed to administered as a single dose of palonosetron, for example, the greater AUC, the larger C.sub.max, the shorter t.sub.max, (the median t.sub.max was 0.5 hour shorter after administration of palonosetron in combination with netupitant), and the longer t.sub.1/2,z.

(76) TABLE-US-00004 TABLE 4 Summary of Palonosetron Pharmacokinetic Parameters Palonosetron 0.75 mg + Parameter Palonosetron 0.75 mg Netupitant 450 mg AUC.sub.0-t [h* μg/L] 67415 (19554) 74230 (24866) AUC.sub.0-inf [h*μg/L] 70813 (20415) 77254 (25402) C.sub.max [μg/L] 1638.4 (415.5) 1863.1 (487.1) t.sub.max (h) 5.02 (4.00; 8.00) 4.50 (3.00; 6.02) t.sub.1/2,z (h) 34.73 (19.61; 70.46) 36.91 (20.23; 56.08) Mean and SD are shown, except for t.sub.max and t.sub.1/2, where median and range are shown.

Example 3: Netupitant+Dexamethasone Drug Interaction Study

(77) The effect of netupitant on orally administered dexamethasone pharmacokinetics was evaluated in this study. This was a randomized, open, 3-period crossover study utilizing an incomplete Latin Square design where subjects were given dexamethasone alone, or oral Netupitant 100 mg., 300 mg. or 450 mg. each given with dexamethasone. Netupitant was given orally on Day 1 only. The dexamethasone regimen for each treatment was 20 mg. orally Day 1, followed by 8 mg. orally every 12 hours from Day 2 through Day 4. Nineteen subjects (12 male and 7 female) completed the study (i.e., all 3 treatment periods).

(78) Mean plasma concentrations of dexamethasone were higher when dexamethasone was co-administered with netupitant (FIG. 4). The increase appeared to be dependant on the netupitant exposure.

(79) The AUC.sub.0-24 (Day 1) of dexamethasone increased 1.5, 1.7 and 1.8-fold with co-administration of 100, 300 and 450 mg. netupitant, respectively. The AUC.sub.24-36 (Day 2) of dexamethasone increased 2.1, 2.4 and 2.6-fold and AUC.sub.84-108 and AUC.sub.84-inf (Day 4) increased 1.7, 2.4 and 2.7-fold, with co-administration of 100, 300 and 450 mg. netupitant, respectively. Dexamethasone C.sub.max on Day 1 was only slightly affected by co-administration of netupitant (1.1-fold increase during co-administration with 100 and 300 mg. netupitant, respectively, and 1.2-fold increase during co-administration with 450 mg. netupitant). C.sub.max on Day 2 and Day 4 was increased approximately 1.7-fold in subjects administered netupitant. Dexamethasone C.sub.min on Days 2-4 was increased approximately 2.8, 4.3 and 4.6-fold with co-administration of 100, 300 and 450 mg. netupitant, respectively. This clearly shows that the co-administration of netupitant and dexamethasone enhances the bioavailability of dexamethasone and provides a better therapeutic window of dexamethasone.

Example 4: Netupitant PET Receptor Occupancy Study

(80) This was a randomized, open-label, positron emission tomography (PET) study using 11C-GR205171 as tracer in 6 healthy male volunteers (2 per dose level) receiving single doses of netupitant (100, 300 or 450 mg) to investigate the degree of occupancy of NK.sub.1 receptors in human brain, and to determine the relationship between plasma concentration of netupitant and NK.sub.1 receptor occupancy (RO).

(81) The anticipated high NK.sub.1-RO (90% or higher) close to the expected C.sub.max (6 hours post dose) was reached for striatum, occipital cortex, frontal cortex and anterior cingulate in 3 of 6 subjects of whom 1 received 300 mg. and 2 received 450 mg. of netupitant as a single oral dose.

(82) All doses showed a relatively long duration of blockade of NK.sub.1 receptors and the decline over time was dose dependent. In the 100 mg. dose group, 4 of 6 regions still had a mean NK.sub.1-RO over 70% at 96 hours post dose. In the highest dose group (450 mg), 5 of 6 regions had a mean NK.sub.1-RO of 80% or higher at 96 hours post dose. A comparison of the results for the dose groups (100 mg., 300 mg. and 450 mg) showed a consistent but small increase in NK.sub.1-RO.sub.s with increasing netupitant dose. (FIG. 5)

Example 5: Clinical Efficacy Study

(83) A phase 2 trial evaluated three single doses of netupitant combined with palonosetron and dexamethasone compared to palonosetron alone and dexamethasone to obtain dose ranging information for netupitant used with oral palonosetron in the CINV patient population.

(84) The objective of the study was to compare the efficacy and safety of three single oral doses of netupitant combined with oral palonosetron and given with dexamethasone, versus oral palonosetron-alone given with dexamethasone (without netupitant) for the prevention of highly emetogenic chemotherapy (HEC)-induced nausea and vomiting. The FDA-approved oral aprepitant regimen given with IV ondansetron and dexamethasone was included in the study as an active comparator for exploratory purposes. The FDA-approved oral palonosetron 0.5 mg. dose was used in each applicable treatment group in this study.

(85) This was a multicenter, randomized, double-blind, double-dummy, parallel group, stratified study. Eligible patients were randomized (stratified by gender) to one of the following treatment groups:

(86) Group 1—0.5 mg. oral palonosetron on Day 1 (with an oral dexamethasone standard regimen: 20 mg. on Day 1 and 8 mg. BID from Day 2 through Day 4)

(87) Group 2—100 mg. oral netupitant plus 0.5 mg. oral palonosetron on Day 1 (with an oral dexamethasone adjusted regimen*: 12 mg. on Day 1 and 8 mg. daily from Day 2 through Day 4)

(88) Group 3—200 mg. oral netupitant plus 0.5 mg. oral palonosetron on Day 1 (with an oral dexamethasone adjusted regimen*: 12 mg. on Day 1 and 8 mg. daily from Day 2 to Day 4)

(89) Group 4—300 mg. oral netupitant plus 0.5 mg. oral palonosetron on Day 1 (with dexamethasone adjusted regimen*: 12 mg. on Day 1 and 8 mg. daily from Day 2 to Day 4)

(90) Group 5—125 mg. oral aprepitant plus IV ondansetron 32 mg. (both on Day 1) then 80 mg. oral aprepitant on Day 2 and Day 3, (all with an oral dexamethasone adjusted regimen: 12 mg. on Day 1 and 8 mg. daily from Day 2 through Day 4)

(91) In addition, a Group 6 was added to the analysis for comparative purposes, based on the results reported by Grunberg et al., Support Cancer Care (2009) 17:589-594:

(92) Group 6—285 mg. oral aprepitant plus 20 mg. oral dexamethasone plus 0.2 mg. palonosetron i.v. (all on Day 1) then 80 mg. oral aprepitant

(93) The primary efficacy endpoint was the complete response rate (defined as no emetic episodes, no rescue medication) within 120 hours after the start of the highly emetogenic chemotherapy administration. Secondary efficacy endpoints were: Complete response for the 0-24 hour interval (acute phase); and for the 25-120 hour interval (delayed phase); Complete protection (defined as no emesis, no rescue therapy, no significant nausea); Total control (defined as no emesis, no rescue therapy and no nausea); No nausea (maximum VAS <5 mm); No significant nausea (maximum VAS <25 mm); No rescue medication; No emesis. These endpoints were evaluated for the 0-120 hour interval (overall), acute and delayed phase. Time to first emetic episode, Time to first rescue medication, Time to treatment failure (based on time to the first emetic episode or time to the first rescue medication, whichever occurs first); Severity of nausea for the overall, acute and delayed phase; ⋅Patient global satisfaction with anti-emetic therapy by means of VAS for each 24 hour interval.

(94) Complete response rates are summarized in Table 5. The percent of patients with complete response over 0-120 hours after start of cisplatin administration was 76.5% in the palonosetron alone group and 87.4%, 87.6%, and 89.6% in the netupitant 100 mg., 200 mg., and 300 mg. groups, respectively. Differences from palonosetron-alone were greater than 10% (10.9% to 13.2%). All doses of netupitant were statistically superior to palonosetron alone (p-value=0.004 for the netupitant 300 mg. combination group).

(95) TABLE-US-00005 TABLE 5 COMPLETE RESPONSE RATE FOR THE OVERALL ACUTE AND DELAYED PHASE: MFAS Population Palo Palo + Netu Palo + Netu Palo + Netu Aprepitant alone 100 mg 200 mg 300 mg Regimen Efficacy endpoint (n = 136) (n = 135) (n = 137) (n = 135) (N = 134) CR, Overall Phase, 0-120 h Percent of Patients 76.5 87.4 87.6 89.6 86.6 Difference from Palo alone (%) 10.9 11.1 13.2 10.1 p-value (*) 0.018 0.017 0.004 0.027 CR, Acute Phase, −24 h Percent of Patients 89.7 93.3 92.7 98.5 94.8 Difference from Palo alone (%) 3.6 3.0 8.8 5.1 p-value (*) 0.278 0.383 0.007 0.114 CR, Delayed Phase, 25-120 h Percent of Patients 80.1 90.4 91.2 90.4 88.8 Difference from Palo alone (%) 10.2 11.1 10.2 8.7 p-value (*) 0.018 0.010 0.018 0.043 (*) p-value from logistic regression analysis, aprepitant p-value from post-hoc logistic regression analysis.

(96) Table 6 summarizes results for main secondary endpoints. In the overall phase, 76.5% of patients in the palonosetron-alone group did not experience emesis, while 87.4, 87.6, and 91.1% of patients did not experience emesis in the netupitant 100 mg., 200 mg. and 300 mg. combination groups, respectively (p<0.05 for all doses).

(97) TABLE-US-00006 TABLE 6 SUMMARY OF SECONDARY EFFICACY RESULTS: PERCENT OF PATIENTS, MFAS POPULATION Palo Palo + Netu Palo + Netu Palo + Netu Aprepitant Palo + Aprep Efficacy alone 100 mg 200 mg 300 mg Regimen 285 mg endpoint (n = 136) (n = 135) (n = 137) (n = 135) (N = 134) (N = 41)** No Emesis Overall 76.5 87.4* 87.6* 91.1* 87.3 Acute 89.7 93.3 92.7 98.5* 94.8 Delayed 80.1 90.4* 91.2* 91.9* 89.6* No Rescue Overall 95.6 97.8 100 98.5 97.8 Acute 97.8 99.3 100 100 100 Delayed 97.1 97.8 100 98.5 97.8 No Nausea Overall 50.7 54.8 62.0 61.5 58.2 32 Acute 75.0 72.6 77.4 80.0 77.6 59 Delayed 53.7 59.3 65.0 68.1* 60.4 41 No Significant Nausea Overall 79.4 80.0 86.1 89.6* 85.8 56 Acute 93.4 94.1 94.2 98.5* 94.0 79 Delayed 80.9 81.5 89.8* 90.4* 88.1 59 Total Control Overall 50.0 54.8 61.3 59.3 56.0 Acute 71.3 71.9 76.6 80.0 74.6 Delayed 52.2 59.3 65.0* 65.9* 58.2 Complete Protection Overall 69.9 76.3 80.3* 83.0* 78.4 51 Acute 87.5 89.6 88.3 97.0* 89.6 76 Delayed 73.5 80.0 87.6* 84.4* 82.1 66 *p-value, 0.05 compared with palonosetron-alone; aprepitant comparisons p-values calculated by post-hoc analysis **As reported by Grunberg et al., Support Cancer Care (2009) 17:589-594

Example 7: Comparative Results of Aprepitant Dosing Regimen

(98) The following Table 8 reports the results observed for an aprepitant dosing regimen, as described in the FDA approved prescribing information for aprepitant, which demonstrates, among other things, that aprepitant has no meaningful effect on nausea. Table 7 reports the dosing regimen:

(99) TABLE-US-00007 TABLE 7 Treatment Regimen Day 1 Day 2 to 4 Aprepitant Aprepitant 125 mg PO Aprepitant 80 mg PO Daily (Days 2 and 3 only) Dexamethasone 12 mg PO Dexamethasone 8 mg PO Daily (morning) Ondansetron 32 mg I.V.

(100) TABLE-US-00008 TABLE 8 Percent of Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group and Phase for Study 1-Cycle 1 Aprepitant Standard Regimen Therapy (N = 260)† (N = 261)† ENDPOINTS % % p-Value PRIMARY ENDPOINT Complete Response Overall‡ 73 52 <0.001 OTHER PRESPECIFIED ENDPOINTS Complete Response Acute phase.sup.1 89 78 <0.001 Delayed Phase.sup.2 75 56 <0.001 Complete Protection Overall 63 49 0.001 Acute phase 85 75 NS* Delayed phase 66 52 <0.001 No Emesis Overall 78 55 <0.001 Acute phase 90 79 0.001 Delayed phase 81 59 <0.001 No Nausea Overall 48 44 NS** Delayed phase 51 48 NS** No Significant Nausea Overall 73 66 NS** Delayed phase 75 69 NS** †N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one post-treatment efficacy evaluation. ‡Overall: 0 to 120 hours post-cisplatin treatment. .sup.1Acute phase: 0 to 24 hours post-cisplatin treatment. .sup.2Delayed phase: 25 to 120 hours post-cisplatin treatment. *Not statistically significant when adjusted for multiple comparisons.

(101) Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.