EP3013336A1 - Utilisation de serlopitant, antagoniste du récepteur nk -1, dans le traitement du prurit - Google Patents

Utilisation de serlopitant, antagoniste du récepteur nk -1, dans le traitement du prurit

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Publication number
EP3013336A1
EP3013336A1 EP14744671.0A EP14744671A EP3013336A1 EP 3013336 A1 EP3013336 A1 EP 3013336A1 EP 14744671 A EP14744671 A EP 14744671A EP 3013336 A1 EP3013336 A1 EP 3013336A1
Authority
EP
European Patent Office
Prior art keywords
serlopitant
cream
administered
day
ointment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14744671.0A
Other languages
German (de)
English (en)
Inventor
Xiaoming Zhang
Edward F. Schnipper
Andrew J. PERLMAN
James W. Larrick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vyne Therapeutics Inc
Original Assignee
Tigercat Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US13/925,509 external-priority patent/US8906951B1/en
Application filed by Tigercat Pharma Inc filed Critical Tigercat Pharma Inc
Publication of EP3013336A1 publication Critical patent/EP3013336A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to methods for treating acute or chronic pruritus with an NK-1 receptor antagonist.
  • the invention further relates to pharmaceutical compositions comprising an NK-1 receptor antagonist.
  • Pruritus or itch
  • itch is an uncomfortable skin sensation that provokes a desire to scratch.
  • itch may be acute, for example, from an insect sting, chronic pruritus originates from many different causes. It is a seriously debilitating condition, comparable to chronic pain, which negatively impacts quality of life.
  • Chronic pruritus is also a prevalent symptom in cutaneous T-cell lymphoma (68-93%), a disease that includes mycosis fungoides and Sezary syndrome (N. Meyer et ai, Acta Derm. Venereol., 2010, 90:12-17). Pruritus is the most common dermatological complaint in elderly patients (S. Beauregard and B. A. Gilchrest, Arch.
  • Antihistamines can sometimes effectively treat itch due to acute urticaria, but many chronic pruritic diseases respond poorly to conventional H1 receptor antagonists (Tey H.L. and G. Yosipovitch; Br. J. Dermatol., 2011, 165(1 ):5-17). In addition to marginal efficacy, antihistamines can also cause intolerable drowsiness.
  • Other current therapies possess various limitations. For example,
  • anticonvulsants such as gabapentin inhibit spinal mechanisms in the perception of itch, but their use is limited due to their slow onset of action (5-6 weeks) (Metz and Stander, 2008).
  • Opiate receptor antagonists such as naloxone, nalmefene, and naltrexone decreased pruritus symptoms in patients with liver and kidney disease, although significant central nervous and gastrointestinal side effects occurred (Metz and Stander, 2008; N. V. Bergasa etal., Hepatology, 2006, 44(5): 1317-23).
  • Substance P the endogenous ligand for the neurokinin-1 (NK-1) receptor
  • NK-1 neurokinin-1
  • Intradermal injection of substance P elicits an itch sensation in human subjects, and an associated itch response in mice.
  • the substance P-induced itch-associated response in mice is not inhibited by antihistamines (B.
  • Aprepitant (Emend®), an NK-1 receptor antagonist, is approved by the FDA for use in the prevention of chemically induced nausea and vomiting (emesis) after chemotherapy.
  • Duval and Dubertret first reported that oral aprepitant (80 mg daily) had utility in treating pruritus in three patients with Sezary syndrome (N. Engl. J. Med., 2009, 361(14):1415-6). Torres et al. disclosed similar results (J. Am. Acad. Dermatol., 2012; 66(1):e14-5). Stander et al.
  • aprepitant is generally well-tolerated, it is extremely expensive, limiting its use in chronic pruritus (Tey, 2011). Further, aprepitant is a moderate inhibitor as well as an inducer of CYP3A4 and CYP2C9, indicating that drug-drug interactions with chemotherapeutic agents and corticosteroids must be considered (Torres, 2012).
  • cytochrome P450 3A4 isoform cytochrome P450 3A4 isoform
  • tyrosine-kinase inhibitors an enzyme involved in the metabolism of a range of commonly prescribed drugs, including tyrosine-kinase inhibitors, either inducing or inhibiting the CYP-3A4, depending on which drugs are given concomitantly.
  • Tyrosine-kinase inhibitors do not induce frequent nausea and emesis; therefore, clinical experience with concomitant administration of aprepitant and these drugs is scarce.
  • the pharmacokinetics of tyrosine-kinase inhibitors varies widely between patients, and drug-drug interactions are common (O. Mir and R. Coriat, The Lancet, 2012, 13:964-965). Thus, the need for additional, safe treatments for acute and chronic pruritus exists.
  • this invention provides a method of treating pruritus in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of 3- U3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl
  • the therapeutically effective amount comprises a dosage of 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg one or more times a day.
  • the therapeutically effective amount comprises a dosage of 0.25 mg, 1 mg, or 5 mg once a day.
  • the therapeutically effective amount comprises a dosage of from about 0.1 mg to about 30 mg or from about 1 mg to about 7.5 mg. In another embodiment, the therapeutically effective amount is administered orally in the form of a tablet. In a further embodiment, the
  • therapeutically effective amount is administered once a day at bedtime. In another embodiment, the therapeutically effective amount is administered once a day, once every other day, once every third day, once every fourth day, or once a week. In other embodiments, serlopitant is administered under a chronic dosing regimen. In some embodiments, a therapeutically effective amount of serlopitant is administered over a period of at least 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months or longer.
  • this invention provides a method of treating pruritus whereby 3- [(3aR,4R,5S,7aS)-5-[(1 R)-1 -[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1 ,3,3a,4,5,6,7,7a- octahydroisoindol-2-yl]cyclopent-2-en-1-one (serlopitant) or a pharmaceutically acceptable salt , solvate or polymorph thereof is administered to a patient in need of such treatment according to a schedule, wherein a least one loading dose is first administered, and, second, at least one therapeutically effect maintenance dose is administered.
  • the loading dose is five times, four times, three times, or two times the maintenance dose. In another embodiment, the loading dose is three times the maintenance dose. In a further embodiment, the loading dose is administered on day 1 and the maintenance dose is administered on day 2 and thereafter. In another embodiment, the loading dose and the maintenance dose are administered at bedtime. In another embodiment, the method further comprises administering a second loading dose prior to administering the maintenance dose. In one embodiment, the loading dose is three times the maintenance dose and the second loading dose is two times the maintenance dose. In a further embodiment, the therapeutically effective maintenance dose is 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg,
  • the therapeutically effective maintenance dose comprises a dosage of 0.25 mg, 1 mg, or 5 mg administered once a day. In a further embodiment, the therapeutically effective
  • the maintenance dose comprises a dosage from about 0.1 mg to about 30 mg or from about 1 mg to about 7.5 mg.
  • the therapeutically effective maintenance dose is administered once a day, once every other day, once every third day, once every fourth day, or once a week.
  • serlopitant is administered under a chronic dosing regimen.
  • a therapeutically effective maintenance dose of serlopitant is administered over a period of at least 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months or longer.
  • serlopitant is administered orally.
  • this invention provides a pharmaceutical composition for the treatment of pruritus comprising 3-[(3aR,4f?,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)- 1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-one or a pharmaceutically acceptable salt, solvate or polymorph thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated as a tablet comprising Compound 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof and one or more diluents, disintegrants, surfactants or lubricants.
  • the composition comprises a capsule filled with a solution comprising Compound 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof and an amphiphilic agent.
  • the amphiphilic agent is a fatty acid ester of glycerol, propylene glycol or sorbitol.
  • the pharmaceutical composition comprises 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg,
  • the composition comprises 0.25 mg, 1 mg, or 5 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof.
  • this invention provides a method of treating acute or chronic pruritus in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition comprising 3-[(3a ?,4 ?,5S,7aS)-5-[(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1 I 3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent- 2-en-1-one or a pharmaceutically acceptable salt, solvate or polymorph thereof and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising 3-[(3a ?,4 ?,5S,7aS)-5-[(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1 I 3,3a,4,5,6,7,7a-octahydr
  • the method involves treatment with a pharmaceutical composition formulated as a tablet comprising Compound 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof and one or more diluents, disintegrants, surfactants or lubricants.
  • the method involves administration of a composition comprising a capsule filled with a solution comprising Compound 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof and an amphiphilic agent.
  • the amphiphilic agent is a fatty acid ester of glycerol, propylene glycol or sorbitol.
  • the method involves treatment with a pharmaceutical composition
  • a pharmaceutical composition comprising 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof.
  • the composition comprises 0.25 mg, 1 mg, or 5 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof.
  • a pruritus-associated condition is treated by administration of serlopitant (Compound 1) and an additional antipruritic agent.
  • a sleep problem or disorder is treated by administration of serlopitant, optionally in combination with an additional sleep-aiding agent.
  • FIG. 1 depicts a synthetic scheme for serlopitant, Compound 1.
  • FIG. 2 illustrates a Franz diffusion cell for studying skin permeation of a drug in vitro.
  • FIG. 3 shows the cumulative release of serlopitant from topical formulations B and C into the receptor chamber of a Franz diffusion cell at various time points in an in vitro study of skin permeation.
  • FIG. 4 shows the amount of serlopitant (called "VPD737”) retained in the skin at the end of the Franz diffusion cell study.
  • Each bar represents ug of serlopitant g of skin in 250 urn skin layers.
  • the bars from left to right represent the amount of serlopitant retained in skin layers from the stratum comeum to the dermis.
  • Serlopitant is a neurokinin-1 (NK-1) receptor antagonist.
  • the present invention provides a method for treating chronic pruritus and related conditions using serlopitant or a pharmaceutically acceptable salt or hydrate thereof.
  • serlopitant refers to the compound of Compound 1:
  • the I.U.P.A.C. name for the compound is 3-[(3aR,4R,5S,7aS)-5-[(1 )-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopem 2-en-1-one.
  • Compound 1 may be named 3-[(3aR,4R,5S,7aS)-5- ⁇ (1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxyH-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one.
  • any of these designations for Compound 1 may be interchangeably used and have the same meaning.
  • the invention also encompasses the racemic form of serlopitant (Compound 1).
  • NK-1 receptor antagonist an inhibitor of tachykinin and, in particular, of substance P
  • Neurokinin receptors are part of the larger family of G-protein coupled receptors that elicit many of their effects via activation of the inositol phosphate signal transduction pathway.
  • NK-1 receptors are present in both the central and peripheral nervous system and in vascular endothelial cells, muscle and cells of the immune system.
  • Compound 1 is unusually selective (>39,000 fold) for the cloned human NK-1 receptor over the cloned human NK-2 and NK-3 receptors, as demonstrated using Chinese hamster ovary cells stably expressing the respective receptors (Jiang et al., 2009). Jiang et al. showed that serlopitant binds to the human NK-1 receptor with a of 46 pM and that it displaces substance P binding at the same receptor with an IC 50 of 61 pM.
  • Compound 1 is a weak reversible inhibitor of human CYP-3A4, 2C8, 2C9, 2C19, 2D6, and 1A2 enzymes, the IC 50 values of which are 39, 58, 30, 29, 35, and >100 ⁇ , respectively.
  • Serlopitant did not significantly induce CYP-3A4 mRNA in three individual preparations of human hepatocytes. These data suggest that serlopitant will have minimal drug-drug interaction liability in humans and that any drug-drug interactions will be reduced in comparison with other NK-1 receptor antagonists.
  • Serlopitant has been disclosed as a treatment for emesis and for urinary incontinence (U.S. Patent Nos. US 7,217,731, US 7,345,083, US 7,544,815, US 7,645,790, and US 7,893,091, the disclosures of which are herein incorporated by reference; U.S. Published
  • Tolterodine was numerically more effective than serlopitant at all efficacy end points and statistically significantly more effective than placebo.
  • Serlopitant was not associated with the adverse experience of dry mouth common in patients receiving tolterodine, a muscarinic antagonist.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '- dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol,
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, ethanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • solvate refers to an aggregate that consists of a solute ion or molecule with one or more solvent molecules.
  • solute ion or molecule include one or more solvent molecules.
  • soluteates include hydrates, that is, aggregates of a compound of interest with water. It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the solvates.
  • polymorph refers to a crystalline form of a compound that can crystallize in different forms.
  • the invention also encompasses polymorphs of serlopitant.
  • polymorphs of serlopitant include without limitation anhydrous crystalline Forms I and li of free base serlopitant as disclosed in US Pat. App. Pub. No. 2009/0270477 to Kuethe et al.
  • Form I is characterized by diffraction peaks obtained from X-ray powder diffraction pattern corresponding to d-spacings of 10.4, 9.9, 9.2, 5.5, 5.0, 4.1, 3.9, 3.6 and 3.5 angstroms.
  • Form II is characterized by diffraction peaks obtained from X-ray powder diffraction pattern corresponding to d-spacings of 7.7, 5.3, .9, 4.8, 4.6, 4.2, 3.9, 3.8 and 2.8 angstroms.
  • US 2009/0270477 is incorporated herein by reference in its entirety.
  • Serlopitant may be prepared as described by Jiang ef al. (J. Med. Chem. 2009, 52:3039-3046), which is herein incorporated by reference in its entirety.
  • the method of Kuethe ef al. as described in U.S. Patent No. 7,544,815, or Bunda ef a/., as described in U.S. Patent No. 7,217,731, both of which are herein incorporated by reference in their entirety, may be used.
  • compositions containing serlopitant or a pharmaceutically acceptable salt, solvate or polymorph thereof as the active ingredient may be advantageously used to treat chronic pruritus. While it is possible for serlopitant or a pharmaceutically acceptable salt, solvate or polymorph thereof to be administered alone, it is preferable to present it as a formulation.
  • the compositions, or dosage forms may be administered or applied singly, or in combination with other agents.
  • the formulations may also deliver serlopitant to a patient in combination with another pharmaceutically active agent.
  • composition as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional pharmaceutically acceptable carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • Said compositions are prepared according to conventional mixing, granulating, or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a tablet may be made by compressing or molding the active ingredient optionally with one or more pharmaceutically acceptable ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active, or dispensing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered active ingredient and a suitable carrier moistened with an inert liquid diluent.
  • compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • a pharmaceutical composition of the present invention may comprise a liquid-filled capsule dosage form in which the active ingredient is in solution in certain combinations of liquid and semi-solid excipients.
  • the invention is directed to a solution comprising the active agent 3-[(3a ?,4R5S,7aS)-5- ⁇ (1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy ⁇ -4-(4-fluorophenyl)-octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (Compound 1) or a pharmaceutically acceptable salt, solvate or polymorph thereof, and an amphiphilic agent, said amphiphilic agent being a fatty acid ester of glycerol, propylene glycol or sorbitol, as described in U.S. Published Application No.
  • the amphiphilic agent consists essentially of mono- and di- glycerides of C8 to C12 saturated fatty acids and mixtures thereof.
  • compositions for oral administration may also be formulated as aqueous suspensions containing the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Oily suspensions may be formulated by suspending the active ingredient in a suitable oil.
  • Oil-in-water emulsions may also be employed.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • the active ingredient of the present invention may be administered in an oral sustained release formulation.
  • sustained release refers to release of an active agent from a dosage form at a rate effective to achieve a therapeutic amount of the agent, or active metabolite thereof, in the systemic blood circulation over a prolonged period of time relative to that achieved by oral administration of a conventional formulation of the agent. Release of the agent occurs over an extended period of hours, for example, over a period of at least 6 hours, over a period of at least 8 hours, over a period of at least 12 hours, or over a period of at least 24 hours.
  • Suitable topical formulations and dosage forms include ointments, creams, gels, lotions, pastes, and the like, as described in Remington: The Science and Practice of Pharmacy (21 st Edition,
  • Ointments are semi-solid preparations that are typically based on petrolatum or other petroleum derivatives.
  • the specific ointment base to be used is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like.
  • Creams are viscous liquids or semisolid emulsions, either oi -in-water or water-in-o ' il. Cream bases are water- washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also called the "internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules (polymers) distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol such as ethanol or isopropanol and, optionally, an oil.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.
  • Lotions are preparations to be applied to the skin surface without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of finely divided solids and will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin.
  • Pastes are semisolid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from single-phase aqueous gels.
  • Various additives may be included in the topical formulations.
  • solvents including relatively small amounts of alcohol, may be used to solubilize certain drug substances.
  • Other optional additives include opacifiers, antioxidants, fragrance, colorant, gelling agents, thickening agents, stabilizers, surfactants and the like.
  • Other agents may also be added, such as antimicrobial agents, to prevent spoilage upon storage, i.e., to inhibit growth of microbes such as yeasts and molds.
  • a permeation enhancer in the formulation.
  • the formulation may also contain irritation-mitigating additives to minimize or eliminate the possibility of skin irritation or skin damage resulting from the drug, the enhancer, or other components of the dosage form.
  • the formulations may also contain ether physiologically acceptable excipients or other minor additives, such as fragrances, dyes, emulsifiers, buffers, cooling agents (e.g. menthol), antibiotics, stabilizers or the like.
  • one component may serve more than one function.
  • the concentration of the active agent in a topical formulation can vary a great deal, and will depend on a variety of factors, including the disease or condition to be treated, the nature and activity of the active agent, the desired effect, possible adverse reactions, the ability and speed of the active agent to reach its intended target, and other factors within the particular knowledge of the patient and physician.
  • the formulations will typically contain on the order of about 0.1 wt % to 50 wt % active agent, preferably about 0.1 wt % to 5 wt % active agent, optimally about 5 wt % to 20 wt % active agent.
  • a topical dosage form of serlopitant is formulated as a buccal or sublingual tablet or pill.
  • Advantages of a buccal or sublingual tablet or pill include avoidance of first- pass metabolism and circumvention of gastrointestinal absorption.
  • the buccal or sublingual tablet or pill can contain suitable excipients, including without limitation any combination of fillers and diluents (e.g., mannitol and sorbitol), binding agents (e.g., sodium carbonate), wetting agents (e.g., sodium carbonate), disintegrants (e.g., crospovidone and croscarmellose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium stearyl fumarate), stabilizers (e.g., sodium bicarbonate), flavoring agents (e.g., spearmint flavor), sweetening agents (e.g., sucralose), and coloring agents (e.g., yellow iron oxide).
  • the buccal or sublingual tablet or pill containing serlopitant can be used to treat, e.g., any pruritus- associated condition described herein.
  • the pharmaceutical compositions of the present invention may be formulated as a depot formulation for administration via intramuscular or subcutaneous injection.
  • Depot formulations are efficient, well-tolerated, sustained or delayed release compositions of the active ingredient that are therapeutically effective for a number of weeks, such as at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks or more.
  • additional ingredients may be used in the depot formulations of the present invention including surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fillers, solvents, buffers, stabilizers, lubricants, and thickening agents.
  • a combination of additional ingredients may also be used.
  • the amount of the active ingredient in a depot formulation will depend upon the severity of the pruritus being treated.
  • compositions of the present invention may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • unit dosage form is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages.
  • Typical examples of unit dosage forms are tablets or capsules for oral administration.
  • compositions of the present invention may also be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient.
  • kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
  • Topical Compositions Comprising Serlopitant
  • Topical formulations for application to the skin or mucosa can be useful for treatment of conditions of the upper skin or mucosal layers and for transdermal or transmucosal administration of an active agent to the local tissue underlying the skin or mucosa and, if desired, into the blood for systemic distribution.
  • Advantages of topical administration can include avoidance of first-pass metabolism, circumvention of gastrointestinal absorption, delivery of an active agent with a relatively short biological half-life, more controlled release of the active agent, administration of a more uniform plasma dosing of the active agent, and improvement in user compliance.
  • compositions suitable for topical administration include without limitation liquid or semi-liquid preparations such as sprays, gels, liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, foams, ointments and pastes, and solutions or suspensions such as drops (e.g., eye drops, nose drops and ear drops).
  • a topical composition comprises an active agent dissolved, dispersed or suspended in a carrier.
  • the carrier can be in the form of, e.g., a solution, a suspension, an emulsion, an ointment or a gel base, and can contain, e.g., petrolatum, lanolin, a wax (e.g., bee wax), mineral oil, a long-chain alcohol, polyethylene glycol or polypropylene glycol, a diluent (e.g., water and/or an alcohol [e.g., ethanol or propylene glycol]), an emulsifier, a stabilizer or a thickening agent, or a combination thereof.
  • petrolatum e.g., petrolatum, lanolin
  • a wax e.g., bee wax
  • mineral oil e.g., mineral oil
  • a long-chain alcohol e.g., polyethylene glycol or polypropylene glycol
  • a diluent e.g., water and/or an alcohol [e.g., ethanol or prop
  • a topical composition can include, or a topical formulation can be administered by means of, e.g., a transdermal patch, a microneedle patch or an iontophoresis device.
  • a transdermal patch can contain, e.g., a microporous membrane made of a suitable material (e.g., cellulose nitrate or acetate, propylene or a polycarbonate), a skin adhesive and backing material.
  • a topical composition can deliver the active agent transdermal ⁇ (including percutaneously and transmucosally) via a concentration gradient or an active mechanism (e.g., ionospheres).
  • Topical Compositions Comprising a Permeation Enhancer
  • a topical composition comprises seriopitant and a permeation enhancer.
  • the composition can optionally contain an additional therapeutic agent.
  • the composition contains seriopitant in free base form.
  • the permeation enhancer increases the permeability of the skin or mucosa to the therapeutic agent(s).
  • the permeation enhancer is N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate, isopropyl myristate, oleic acid, glyceryl oleate or sodium lauryl sulfoacetate, or a combination thereof.
  • the composition contains on a weight/volume (w/v) basis the permeation enhancer in an amount of about 1-20%, 1-15%, 1-10% or 1-5%.
  • the composition can also contain a surfactant, an azone-like compound, an alcohol, a fatty acid or ester, or an aliphatic thiol.
  • the composition can further contain one or more additional excipients.
  • Suitable excipients include without limitation solubilizers (e.g., C 2 -C 8 alcohols), moisturizers or humectants (e.g., glycerol [glycerin], propylene glycol, amino acids and derivatives thereof, polyamino acids and derivatives thereof, and pyrrolidone carboxylic acids and salts and derivatives thereof), surfactants (e.g., sodium laureth sulfate and sorbitan monolaurate), emulsifiers (e.g., cetyl alcohol and stearyl alcohol), thickeners (e.g., methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and acrylic polymers), and formulation bases or carriers (e.g., polyethylene glycol as an ointment base).
  • solubilizers e
  • the base or carrier of the composition can contain ethanol, propylene glycol and polyethylene glycol (e.g., PEG 300), and optionally an aqueous liquid (e.g., isotonic phosphate-buffered saline).
  • the topical composition can have any suitable dosage form, such as a solution (e.g., eye drop, nose drop or ear drop), a suspension, an emulsion, a cream, a lotion, a gel, an ointment, a paste, a jelly, a foam, a shampoo, or a spray.
  • the composition is applied to the skin or mucosa covering a surface area of about 10-800 cm 2 , 10-400 cm 2 or 0-200 cm 2 .
  • the composition can deliver the therapeutic agent(s) to the skin or mucosa or the underlying tissue.
  • the composition can also be formulated for transdermal administration of the therapeutic agent(s) to the systemic circulation, e.g., as a transdermal patch or a microneedle patch.
  • Topical Compositions Comprising a Permeation Enhancer and a Volatile Liquid
  • a topical composition comprises serlopitant, a permeation enhancer and a volatile liquid.
  • the composition can optionally contain an additional therapeutic agent.
  • the composition contains serlopitant in free base form.
  • the permeation enhancer increases the permeability of the skin or mucosa to the therapeutic agent(s).
  • the permeation enhancer is selected from the group consisting of C 8 - C 18 alkyl aminobenzoates (e.g., C 8 -C 18 alkyl p-aminobenzoates), C 8 -Ci 8 alkyl dimethylaminobenzoates (e.g., C 8 -C 18 alkyl p-dimethylaminobenzoates), C 8 -Ci 8 alkyl cinnamates, C 8 -Ci 8 alkyl
  • methoxycinnamates e.g., C 8 -C 18 alkyl p-methoxycinnamates
  • C 8 -C 18 alkyl salicylates e.g., C 8 -C 18 alkyl p-methoxycinnamates
  • the permeation enhancer is octyl salicylate, octyl p-dimethylaminobenzoate or octyl p- methoxycinnamate, or a combination thereof.
  • the volatile liquid can be any volatile, skin- or mucosa-tolerant solvent.
  • the volatile liquid is a C 2 -C 5 alcohol or an aqueous solution thereof, such as ethanol or isopropanol or an aqueous solution thereof.
  • An aerosol propellant e.g., dimethyl ether
  • the volatile liquid functions as a carrier or vehicle of the composition.
  • the composition can optionally contain a thickening agent.
  • thickening agents include cellulosic thickening agents (e.g., ethyl cellulose, hydroxypropyl cellulose and
  • hydroxypropyl methylcellulose povidone
  • polyacrylic acids/polyacrylates e.g., Carbopol® polymers
  • Sepigel® polyacrylamide/isoparaffin/laureth-7
  • Gantrez® series of polymethyl vinyl ether/maleic anhydride copolymers e.g., butyl ester of PMV/MA copolymer Gantrez® A-425.
  • the composition contains on a weight basis about 0.5-10%, 0.5-5% or 1- 5% of serlopitant, about 1-20%, 1- 5% or 1-10% of the permeation enhancer, and about 40-98%, 45- 95%, 50-90% or 60-80% of the volatile liquid.
  • the composition optionally contains on a weight basis about 1-40%, 1-30%, 1-20% or 5-20% water and/or about 0.1-15%, 0.5-10% or 1-5% of a thickening agent.
  • a topical spray composition contains about 0.5-5% w/v of serlopitant, about 2-10% w/v of octyl salicylate or octyl p-methyoxycinnamate, and about 95% aqueous ethanol as the carrier.
  • a topic gel composition comprises about 0.5-5% w/v of serlopitant, about 1-10% w/v of octyl salicylate or octyl p-methyoxycinnamate, about 0.5- 5% w/v of a Carbopol® polyacrylic acid, and about 70% aqueous ethanol as the carrier, and optionally about 1-10% w/v of a basic solution (e.g., 0.1 N NaOH).
  • a basic solution e.g., 0.1 N NaOH
  • a topical lotion composition contains about 0.5-5% w/v of serlopitant, about 1-10% w/v of octyl salicylate or octyl p- methyoxycinnamate, about 1-5% w/v of ethyl cellulose or hydroxypropyl cellulose, and about 90% aqueous ethanol as the carrier.
  • the composition can further comprise other excipients, such as a compounding agent (e.g., paraffin oil, silicone oil, a vegetable oil, or a fatty ester such as isopropyl myristate), a diluent, a co- solvent (e.g., acetone or a glycol ether such as diethylene glycol monoethyl ether), an emulsifier, a surfactant (e.g., an ethoxylated fatty alcohol, glycerol mono stearate or a phosphate ester), a stabiliser, an antioxidant or a preservative (e.g., a hydroxybenzoate ester), or a combination thereof.
  • a co-solvent and/or a surfactant can be used to maintain the therapeutic agent(s) in solution or suspension at the desired concentration.
  • the topical composition can have any suitable dosage form, such as a cream, a lotion, a gel, an ointment, a mousse, a spray or aerosol, or any transdermal device (e.g., a patch) that administers a drug by absorption through the skin or mucosa.
  • the topical composition is applied to the skin or mucosa covering a surface area of about 10-800 cm 2 , 0-400 cm 2 or 0-200 cm 2 .
  • Topical Compositions Comprising a Permeation Enhancer and Another Excipient
  • a topical composition comprises serlopitant, a permeation enhancer, and at least one of a lipophilic solvent, a formulation base and a thickener.
  • the composition contains a lipophilic solvent and a formulation base, or the same substance can function as both a lipophilic solvent and a formulation base.
  • the composition contains a lipophilic solvent, a formulation base and a thickener.
  • the composition can optionally comprise an additional therapeutic agent.
  • the composition contains serlopitant in free base form.
  • the permeation enhancer increases the permeability of the skin or mucosa to the therapeutic agent(s).
  • permeation enhancers include dimethyl sulfoxide (DMSO), decylmethylsulfoxide, laurocapram, pyrrolidones (e.g., 2-pyrrolidone and N-methyl-2-pyrrolidine), surfactants, alcohols (e.g., oleyl alcohol), polyethylene glycol (e.g., PEG 400), diethylene glycol monoethyl ether, oleic acid, and fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate).
  • DMSO dimethyl sulfoxide
  • decylmethylsulfoxide laurocapram
  • pyrrolidones e.g., 2-pyrrolidone and N-methyl-2-pyrrolidine
  • surfactants
  • Non-limiting examples of liphophilic solvents include lipophilic alcohols (e.g., hexylene glycol, octyldodecanol, oleyl alcohol and stearyl alcohol), polyethylene glycol (e.g., PEG 100, PEG 300, PEG 400 and PEG 3350), diethylene glycol monoethyl ether, polysorbates (e.g., Tween® 20 to 80), Labrasol®, fatty acid esters (e.g., isopropyl myristate and diisopropyl adipate), diethyl sebacate, propylene glycol monocaprylate, propylene glycol laurate, mono- and di-glycerides (e.g., Capmul® MC ), medium-chain triglycerides, caprylic capric triglyceride, glyceryl monocaprylate, glyceryl monooleate, glyceryl mono-linole
  • a liphophilic solvent may also function as a formulation base or carrier.
  • polyethylene glycol e.g., from PEG 100 to PEG 3500, such as PEG 300, PEG 400 and PEG 3350
  • PEG 100 to PEG 3500 such as PEG 300, PEG 400 and PEG 3350
  • PEG 300, PEG 400 and PEG 3350 can function as a liphophilic solvent and a formulation base.
  • the composition can also contain a hydrophilic solvent, such as a Ci-C 5 alcohol (e.g., ethanol, isopropanol, glycerol, propylene glycol and 1 ,2-pentanediol) and/or water.
  • a hydrophilic solvent such as a Ci-C 5 alcohol (e.g., ethanol, isopropanol, glycerol, propylene glycol and 1 ,2-pentanediol) and/or water.
  • the composition can contain a thickener to increase the viscosity and/or the physical stability of the composition.
  • thickeners include without limitation glycerol, stearyl alcohol, and polymers (e.g., polydimethylsiloxane [dimethicone] and Carbopol® polymers).
  • the composition further contains an antioxidant.
  • antioxidants include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherols (e.g., Vitamin E and esters thereof), flavinoids, glutathione, ascorbic acid and esters thereof, DMSO, and chelating agents (e.g., EDTA and citric acid).
  • the topical composition comprises on a w/w basis about 0.5-10% or 1- 5% of serlopitant, about 2-30% or 5-20% of a permeation enhancer, about 20-80% or 30-70% of a lipophilic solvent that may also function as a formulation base, about 0.1-10% or 1-7.5% of a thickener, and about 0.01-2% or 0.05-1% of an antioxidant.
  • a topical composition can contain serlopitant, PEG 400 and/or PEG 3350 as lipophilic solvent(s) and formulation base(s), diethylene glycol monoethyl ether, oleyl alcohol and/or isopropyl myristate as permeation enhancer(s), stearyl alcohol as a thickener, and BHT as an antioxidant.
  • the topical composition can have any suitable dosage form, such as a cream, a lotion, a gel, an ointment, a jelly, a paste, or any transdermal device (e.g., a patch) that administers a drug by absorption through the skin or mucosa.
  • Topical Compositions Comprising a Permeation Enhancer and an Adhesive
  • a topical composition comprises serlopitant, a permeation enhancer and an adhesive.
  • the composition can optionally contain an additional therapeutic agent.
  • the composition contains serlopitant in free base form.
  • the permeation enhancer increases the permeability of the skin or mucosa to the therapeutic agent(s).
  • the permeation enhancer can be, e.g., a fatty acid ester having a fatty acyl chain length of C 8 -C 2 oor C 12 -C 18 and a C C 6 or C 2 -C 4 alcohol component (e.g., isopropanol).
  • the permeation enhancer is isopropyl myristate or isopropyl palmitate.
  • the permeation enhancer is in an amount of about 0.1-20%, 0.5-15%, 1-15%, 2-12% or 4-10% by weight of the composition or the skin-contacting layer of a transdermal patch.
  • the adhesive maintains contact of the topical composition to the skin or mucosa.
  • adhesives include acrylics/acrylates (e.g., polyacrylates, including polyalkyl acrylates and Duro-Tak® polyacrylates), polyvinyl acetate, ethylenevinylacetate copolymers, polysiloxanes, polyurethanes, plasticized polyether block amide copolymers, natural and synthetic rubbers, plasticized styrene-butadiene rubber block copolymers (e.g., Duro-Tak® 87-6173), and mixtures thereof.
  • acrylics/acrylates e.g., polyacrylates, including polyalkyl acrylates and Duro-Tak® polyacrylates
  • polyvinyl acetate ethylenevinylacetate copolymers
  • polysiloxanes polyurethanes
  • plasticized polyether block amide copolymers natural and synthetic rubbers
  • the topical composition can comprise one or more additional excipients.
  • the additional excipient(s) can be, e.g., a diluent, an emollient, a plasticizer, or an agent that reduces irritation to the skin or mucosa, or a combination thereof.
  • the topical composition prior to application to the skin or mucosa is substantially free of water, tetraglycol (glycofurol) and/or a hydrophilic organic solvent (e.g., a C C 5 alcohol).
  • composition can administer the therapeutic agent(s) transdermally (including
  • the topical composition is in the form of a transdermal patch for application to the skin or mucosa.
  • the patch has a skin- or mucosa-contacting layer ("skin-contacting layer" for simplicity) laminated or otherwise attached to a support layer.
  • skin-contacting layer can be covered by a removable release liner before use to protect the skin-contacting surface and to keep it clean until it is applied to the skin or mucosa.
  • the support layer of the patch acts as a support for the skin-contacting layer and as a barrier that prevents loss of the therapeutic agent(s) in the skin-contacting layer to the environment.
  • the material of the support layer is compatible with the therapeutic agent(s), the permeation enhancer and the adhesive, and is minimally permeable to the components of the patch.
  • the support layer can be opaque to protect the components of the patch from degradation via exposure to ultraviolet light.
  • the support layer is also capable of binding to and supporting the adhesive layer, yet is sufficiently pliable to accommodate the movements of the subject using the patch.
  • the material of the support layer can be, e.g., a metal foil, a metalized polyfoil, or a composite foil or film containing a polymer (e.g., a polyester [such as polyester terephthalate] or aluminized polyester, polyethylene, polypropylene,
  • a polymer e.g., a polyester [such as polyester terephthalate] or aluminized polyester, polyethylene, polypropylene,
  • the release liner can be made of the same material as the support layer, or can be a film coated with an appropriate release surface.
  • Pruritus is a physiological perception within the sensory neuronal network in the skin which, along with pain and physical or mechanical stimuli, can serve as a warning system against potential bodily threats. Itching is an unpleasant sensation that can lead to scratching, but is independent of pain.
  • IFSI International Federation for the Study of Itch
  • the International Federation for the Study of Itch (IFSI) defines chronic pruritus (as opposed to acute pruritus) as itching that lasting six weeks or longer (S. Stander et al., Acta Derm. Venereol., 2007, 87(4):291-4).
  • IFSI International Federation for the Study of Itch
  • Chronic pruritus can seriously diminish the quality of life in its sufferers as it can be intractable and incapacitating. It is a seriously debilitating condition, comparable to chronic pain, which can lead to frustration, desperation and depression. Moreover, chronic scratching often produces open skin lesions, subject to primary or secondary infection, scarring and potential disfigurement. Chronic pruritus is often an indication of underlying disease and is always present in diseases such as urticaria and atopic dermatitis. Diagnosis of the underlying disease is desirable and clinical presentation, patient history, and patient self-evaluation form important parts of such diagnosis.
  • Chronic pruritus on non- inflamed skin may result from dermatological diseases, including atopic diathesis, histosis, porphyria, suburticarial stages of solar injury, cholinergic, adrenergic urticaria, initial stage of mastocytosis, bullous pemphigoid, and Duhring's disease (dermatitis herpetiformis); from endocrine and metabolic disorders, such as chronic renal insufficiency and the dialysis needed treat it, hepatopathies with cholestasis, diabetes mellitus, malabsorption disorders, anorexia, gluten-enteropathies, hyperthyroidism, hypothyroidism, hyperparathyroidism, and perimenopausal pruritus; from infections including HIV infection, parasites, Helicobacter pylori, and helminth-related; from hemotological and
  • lymphoproliferative diseases such as iron deficiency, polycythaemica vera, hypereosinophilia syndrome, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, plasmocytoma, and systemic mastocytosis; from solid malignant tumors including cervical, breast, prostate or large intestinal cancer, and carcinoid tumors; from neurological disorders such as brachioradial pruritus, notalgia paraesthetica, post-zoster neuralgia, vulvodynia, neuropathies of various origin, multiple sclerosis, tumors, abscesses, underperfusion, infarctions involving the CNS/spinal cord; from psychogenic disorders such as depression, schizophrenia, and tactile hallucinations; and from intrahepatic cholestasis in pregnant women (pruritus gravidarum).
  • diseases such as iron deficiency, polycythaemica vera, hyper
  • Chronic pruritus on inflamed skin may be observed in patients with inflammatory skin disease including, but not limited to, atopic dermatitis, allergic, irritant contact dermatitis, exsiccation dermatitis, nummular and dyshidrotic dermatitis, lichen planus, lichen sclerosus et atrophicus, polymorphous light eruption psoriasis, Graver's disease, mucinosis, mastocytosis, and urticaria; infectious skin diseases such as mycoses, bacterial and viral infections, scabies, pediculosis, insect bites, and folliculitides; autoimmune skin diseases including Bullous skin disorders, especially dermatitis herpetiformis
  • PUPPP polymorphic eruption of pregnancy
  • PUPPP polymorphic eruption of pregnancy
  • pemphigoid gestationis atopic eruption of pregnancy
  • neoplasias such as cutaneous T-cell lymphoma (especially the erythrodermic form).
  • Prurigo nodularis is a particularly severe form of chronic itching that may treated by methods and compositions of the present invention. Characterized by itchy, excoriated, lichenified papules and nodules, PN can occur at any age, but most often presents in middle-aged and elderly patients on their arms and legs (E. Weisshaar and S. Stander, Acta Derm. Venereol., 2012, 92:532-533).
  • PN PN may result in permanent changes to the skin, including nodular lichenification, hyperkeratosis,
  • Serlopitant alone or in combination with one or more additional antipruritic agents, can be used to treat pruritus (including acute and chronic pruritus) associated with any condition.
  • the itch sensation can originate, e.g., in the peripheral nervous system (e.g., dermal or neuropathic itch) or in the central nervous system (e.g., neuropathic, neurogenic or psychogenic itch).
  • pruritus-associated conditions include without limitation those described elsewhere herein and the following:
  • dermatological disorders and conditions including inflammatory and non-inflammatory skin conditions
  • adult blaschkitis amyloidoses (e.g., primary cutaneous amyloidosis [including macular amyloidosis, lichen amyloidosis and nodular amyloidosis]), burns (e.g., chemical burns and sunburn), dermatitis ⁇ e.g., atopic dermatitis, contact dermatitis (including allergic contact dermatitis, irritant contact dermatitis and photodermatitis), eczema (e.g., autosensitization dermatitis, dermatitis herpetiformis [Duhring's disease], discoid eczema, dyshidrosis [pompholyx], hand eczema, id reaction [generalized eczema], nummular eczema, stasis dermatitis [gravitational eczema], venous
  • prurigo e.g., actinic prurigo, Besnier's prurigo, prurigo nodularis, prurigo pigmentosa and prurigo simplex
  • pruritus ani pruritus scroti
  • pruritus vulvae pruritus vulvae
  • psoriasis e.g., erythrodermic psoriasis, Guttate psoriasis [eruptive psoriasis], psoriasis vulgaris [chronic stationary psoriasis], pustular psoriasis, and pustulosis palmaris et plantaris
  • parapsoriasis e.
  • aging e.g., senile pruritus
  • changes in hormonal balances associated with aging e.g., perimenopause and menopause
  • infections and infestations including but not limited to cercarial dermatitis (swimmer's itch), insect bites and stings (e.g., by ants, bees, chiggers, fleas, lice [including body lice, head lice and pubic lice], mites, mosquitos, spiders, ticks and wasps), scabies, bacterial infections (e.g., abscess, dermatitis gangrenosa, ecthyma, erythrasma, impetigo and Lyme disease), fungal infections (e.g., candidiasis, dermatophytosis, tinea corporis [ringworm of the body], tinea cruris [jock itch] and tinea pedis [athlete's foot]), viral infections ⁇ e.g., herpes (including herpes zoster [shingles] and post-herpetic itch), measles, parvovirus infections (e.g., parvovirus B19),
  • allergens and irritants including but not limited to allergic rhinitis (e.g., pollinosis [including hay fever]), asthma, animal allergens (e.g., cat dander and dog dander), chemical allergens (e.g., acids [e.g., abietic acid and sorbic acid], cosmetics, detergents, dyes, fabric softeners, fungicides, hydroxyethyl starch and latex), food allergens (e.g., milk proteins, peanuts, tree nuts, seafood, spices, preservatives [e.g., nitrates], vitamins [e.g., vitamins A and B], alcohol, caffeine and monosodium glutamate), metal and metal salt allergens (e.g., chromium, cobalt, gold and nickel and salts thereof), plant allergens (e.g., Balsam of Peru and urushiol [e.g., in poison ivy, poison oak and poison sumac]
  • pruritus caused by drugs/medication including but not limited to chloroquine, hydroxyethyl cellulose, hydroxyethyl starch, angiotensin-converting enzyme inhibitors, xanthine oxidase inhibitors (e.g., allopurinol), antibiotics (e.g., isoniazid, neomycin, penicillin, sulfonamides and vancomycin), antifungals (e.g., fluconazole, griseofulvin, itraconazole and ketoconazole), neuroleptics/antipsychotics (e.g., phenothiazines), antiarrhythmic drugs (e.g., amiodarone and quinidine), chemotherapeutic drugs, diuretic drugs (e.g., hydrochlorothiazide), statins (e.g., simvastatin), and drugs (e.g., opioids) that activate the histamine Hi receptor or trigger histamine release; and conditions related to
  • One or more additional antipruritic agents can optionally be used in combination with serlopitant to treat pruritus (including acute and chronic pruritus).
  • antipruritic agents include without limitation:
  • antihistamines including but not limited to antihistamines that inhibit action at the histamine receptor (e.g., acrivastine, antazoline, azelastine, bilastine, brompheniramine, buclizine,
  • histamine receptor e.g., acrivastine, antazoline, azelastine, bilastine, brompheniramine, buclizine
  • bromodiphenhydramine carbinoxamine, cetirizine, chlorpromazine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine,
  • serotonin receptor antagonists including but not limited to 5-HT 2 antagonists (e.g., clozapine, cyproheptadine, ketanserin, pizotifen and quetiapine) and 5-HT 3 antagonists (e.g., alosetron, cilansetron, dolasetron, granisetron, ondansetron, palonosetron and tropisetron), and analogs and derivatives thereof;
  • 5-HT 2 antagonists e.g., clozapine, cyproheptadine, ketanserin, pizotifen and quetiapine
  • 5-HT 3 antagonists e.g., alosetron, cilansetron, dolasetron, granisetron, ondansetron, palonosetron and tropisetron
  • NK-1 receptor antagonists including but not limited to aprepitant, casopitant (GW679769), dapitant, ezlopitant, fosaprepitant, lanepitant (LY-303870), maropitant, netupitant, nolpitant, orvepitant, rolapitant, vestipitant, vofopitant, AV-818, BIIF 1149CL, CP122,721, DNK-333, GSK-424887, L-733060, L-759274, LY-686017, M516102 and TA-5538, and analogs and derivatives thereof;
  • opioid receptor antagonists including but not limited to butorphanol, cyprodime, levallorphan (lorfan or naloxiphan), nalbuphine, nalorphine (lethidrone or nalline), naloxone, naloxol, nalmefene, naltrexone (e.g., naltrexone 1% cream) and naltrexol, and analogs and derivatives thereof;
  • opioid receptor agonists including but not limited to selective kappa opioid receptor agonists (e.g., asimadoiine, bremazocine, dynorphin, enadoline, ketazocine, nalfurafine, salvinorin A, 2- methoxymethyl salvinorin B, 2-ethoxymethyl salvinorin B, 2-fluoroethoxymethyl salvinorin B, spiradoline, tifluadom, BRL-52537, FE 200665, GR-89696, HZ-2, ICI-199,441 , ICl-204,448, LPK-26, U- 50488 and U-69,593), and analogs and derivatives thereof;
  • selective kappa opioid receptor agonists e.g., asimadoiine, bremazocine, dynorphin, enadoline, ketazocine, nalfurafine, salvinorin A, 2- methoxymethyl salvinorin B, 2-eth
  • Janus kinase (JAK) inhibitors including but not limited to JAK1 inhibitors (e.g., GLPG0634 and GSK2586184), JAK2 inhibitors (e.g., lestaurtinib, pacritinib, CYT387 and TG101348), JAK1/JAK2 inhibitors (e.g., baricitinib and ruxolitinib), and JAK3 inhibitors (e.g., tofacitinib), and analogs and derivatives thereof;
  • JAK1 inhibitors e.g., GLPG0634 and GSK2586184
  • JAK2 inhibitors e.g., lestaurtinib, pacritinib, CYT387 and TG101348
  • JAK1/JAK2 inhibitors e.g., baricitinib and ruxolitinib
  • JAK3 inhibitors e.g., tofacitinib
  • immunomodulators and immunosuppressants including but not limited to thalidomide, antimetabolites (e.g., antifolates such as methotrexate), and calcineurin inhibitors (e.g., ciclosporin [cyclosporin], pimecrolimus and tacrolimus), and analogs and derivatives thereof;
  • antimetabolites e.g., antifolates such as methotrexate
  • calcineurin inhibitors e.g., ciclosporin [cyclosporin], pimecrolimus and tacrolimus
  • antidepressants including but not limited to tricyclic antidepressants (e.g., amitriptyline, amitriptylinoxide, amoxapine, dosulepin [dothiepin], doxepin and melitracen), tetracyclic antidepressants (e.g., amitriptyline, amitriptylinoxide, amoxapine, dosulepin [dothiepin], doxepin and melitracen), tetracyclic
  • antidepressants e.g., amoxapine, maprotiline, mazindol, mianserin, mirtazapine and setiptiline
  • selective serotonin reuptake inhibitors SSRIs, e.g., citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline
  • serotonin-norepinephrine reuptake inhibitors SNRIs, e.g., bicifadine, duloxetine, milnacipran, levomilnacipran, sibutramine, venlafaxine, desvenlafaxine and SEP- 227162
  • analogs and derivatives thereof SNRIs, e.g., bicifadine, duloxetine, milnacipran, levomilnacipran, sibutramine, venlafaxine, desvenlafaxine and SEP- 2271
  • anticonvulsants including but not limited to carbamazepine, gabapentin, pregabalin, and valproic acid and salts thereof (e.g., sodium valproate), and analogs and derivatives thereof;
  • corticosteroids including but not limited to hydrocortisone types (e.g., cortisone and derivatives thereof [e.g., cortisone acetate], hydrocortisone and derivatives thereof [e.g., hydrocortisone acetate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, hydrocortisone-17-butyrate and
  • hydrocortisone types e.g., cortisone and derivatives thereof [e.g., cortisone acetate]
  • hydrocortisone and derivatives thereof e.g., hydrocortisone acetate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, hydrocortisone-17-butyrate and
  • betamethasone types e.g., betamethasone and derivatives thereof [e.g., betamethasone dipropionate, betamethasone sodium phosphate and betamethasone valerate], dexamethasone and derivatives thereof [e.g., dexamethasone sodium phosphate], and fluocortolone and derivatives thereof [e.g., fluocortolone caproate and fluocortolone pivalate]
  • halogenated steroids e.g., alclometasone and derivatives thereof [e.g., alclometasone dipropionate], beclometasone and derivatives thereof [e.g.,
  • local anesthetics including but not limited to amides (e.g., articaine, bupivacaine, cinchocaine [dibucaine], etidocaine, levobupivacaine, lidocaine [e.g., lidocaine 2.5-5% cream], prilocaine [e.g., prilocaine 2.5% cream], EMLA [lidocaine 2.5%/prilocaine 2.5% cream], mepivacaine, ropivacaine and trimecaine), esters (e.g., benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine
  • amides e.g., articaine, bupivacaine, cinchocaine [dibucaine], etidocaine, levobupivacaine, lidocaine [e.g., lidocaine 2.5-5% cream]
  • prilocaine e.g., prilocaine 2.5% cream
  • ethers e.g., polidocanol [e.g., polidocanol 3% foam] and pramocaine [pramoxine] [e.g., pramoxine 1% cream]
  • naturally derived local anesthetics e.g., cocaine, eugenol, menthol, saxitoxin, neosaxitoxin and tetrodotoxin
  • counterirritants and cooling agents including but not limited to capsaicin, camphor, mint oil, menthol (e.g., menthol 1-3% cream), and phenol (e.g., in calamine lotion), and analogs and derivatives thereof;
  • moisturizers including but not limited to aqueous moisturizers, low pH moisturizers containing an acid (e.g., lactic acid), and moisturizers containing a humectant that attracts and retains water (e.g., glycerol, sorbitol, lactate, urea, and hyaluronic acid and salts thereof), an occlusive that prevents evaporation ⁇ e.g., oils (e.g., mineral oil and silicone oil [e.g., dimethicone]) and petroleum jelly
  • an emollient that provides partial hydration and occlusion e.g., oils, waxes [e.g., lanolin and paraffin], lipids [e.g., phospholipids, ceramides, triglycerides, glycol stearate, glyceryl stearate, fatty acids and squa!ene], and sterols [e.g., cholesterol and phytosterol]), and analogs and derivatives thereof; and
  • antipruritic agents including but not limited to S-adenosyl methionine, botulinum toxin (e.g., botulinum toxin types A and B), vitamin D and analogs and derivatives thereof (e.g., calcitriol and calcipotriol [calcipotriene]), non-steroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin), cannabinoid receptor agonists (e.g., CB 2 agonists, such as palmitoylethanolamide), inhibitors of cytokines (e.g., antibodies to interleukins, such as IL-31), antagonists of the prostaglandin D 2 receptor (DP-,) and/or the chemoattractant receptor homologous molecule expressed on TH 2 cells (CRTH2) (e.g., TS-022), phosphodiesterase (PDE) inhibitors (e.g., PDE4 inhibitors, such as apremilast), protea
  • a non-sedating antipruritic agent can be used.
  • second-generation and third-generation antihistamines are designed to be nonsedating, or less sedating than first-generation antihistamines.
  • Non-limiting examples of second- generation and third-generation antihistamines include acrivastine, astemizole, azelastine, bepotastine, bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, ketotifen, levocabastine, loratadine, desloratadine, mizolastine, olopatadine, quifenadine, rupatadine and terfenadine.
  • a corticosteroid of moderate or medium potency is used in combination with serlopitant to treat a pruritus-associated condition.
  • corticosteroids having moderate or medium potency include Groups III, IV and V corticosteroids under the 7-group US classification system and Class II corticosteroids under the 4-class European classification system, including without limitation amcinonide 0.1% (e.g., cream), betamethasone dipropionate 0.05% (e.g., Diprosone® cream/ointment), betamethasone valerate 0.1% (e.g., cream/ointment), clobetasone butyrate 0.05% (e.g., Eumovate® cream), desonide 0.05% (e.g., Tridesilon® cream/ointment and DesOwen® cream/ointment), fluocinolone acetonide 0.01-0.2% (e.g., Synalar® cream/ointment and Syne
  • the optional additional antipruritic agent(s) can be administered to a subject suffering from pruritus concurrently with (e.g., in the same composition as serlopitant or in separate compositions) or sequentially to (before or after) administration of serlopitant.
  • Serlopitant and the optional additional antipruritic agent(s) independently can be administered in any suitable mode, including without limitation orally, topically (e.g., dermally/epicutaneously, transdermal ⁇ , mucosally, transmucosally, intranasal ⁇ [e.g., by nasal spray or drop], opthalmically [e.g., by eye drop], pulmonarily [e.g., by inhalation], bucally, sublingually, rectally and vaginally), by injection or infusion (e.g., parenterally, including intramuscularly, subcutaneously, intradermal ⁇ , intravenously/intravascularly, and
  • an antipruritic agent is administered topically (e.g., dermally) if the pruritus is localized, and is administered systemically (e.g., orally or intravenously) if the pruritus is widespread (generalized) or has a systemic cause.
  • serlopitant and/or the optional additional antipruritic agent(s) are administered orally.
  • serlopitant and/or the optional additional antipruritic agent(s) are administered topically (e.g., dermally, mucosally, bucally or sublingually).
  • Serlopitant and the optional additional antipruritic agent(s) independently can be administered in any suitable frequency, including without limitation daily (one, two, three or more times per day), every two days, twice weekly, thrice weekly, weekly, every two weeks, every three weeks, monthly, every two months and every three months.
  • the dosing frequency can depend on, e.g., the mode of
  • a dermal formulation of serlopitant, and/or that of the optional additional antipruritic agent(s), can be applied to the skin of a subject two, three or four times a day.
  • serlopitant is administered under a chronic dosing regimen.
  • serlopitant is administered over a period of at least 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months or longer.
  • topical dosage forms include without limitation creams, ointments, gels, liniments, lotions, suppositories (e.g., rectal and vaginal suppositories), buccal and sublingual tablets and pills, sprays (e.g., dermal and nasal sprays), and drops (e.g., eye, nose and eardrops).
  • oral dosage forms include solid dosage forms (e.g., cachets, capsules and tablets) and liquid dosage forms (e.g., solutions or suspensions in an aqueous liquid and/or a non-aqueous liquid, and oil-in-water liquid emulsions or water-in-oil liquid emulsions).
  • the formulation is in the form of a solution and comprises an antipruritic agent (e.g., a local anesthetic), a vehicle (e.g., a water-based vehicle or sterile water), a buffer, a reducing agent/antioxidant (e.g., sodium metabisulfite if epinephrine is used as a vasoconstrictor) and a preservative (e.g., methylparaben), and optionally a vasoconstrictor (e.g., epinephrine) to increase the duration of the pharmacological effect of the antipruritic agent by constricting the blood vessels, thereby concentrating the antipruritic agent for an extended duration and increasing the maximum dose of the antipruritic agent.
  • an antipruritic agent e.g., a local anesthetic
  • a vehicle e.g., a water-based vehicle or sterile water
  • a buffer e.g., a reducing agent
  • Table 4 provides non-limiting examples of combination therapies employing serlopitant and one or more additional antipruritic agents for the treatment of pruritus associated with various conditions. Table 4 may also show other therapeutic agents used to treat the underlying causes of the conditions. Table 4
  • nalmefene + serotonin antagonist e.g., nalmefene + serotonin antagonist
  • Ultraviolet B + cannabinoid e.g., dronabinol
  • Counterirritant e.g., capsaicin
  • ultraviolet B Uremia uremic pruritus
  • Kappa opioid receptor agonist e.g.,
  • SSRl e.g., paroxetine
  • Serotonin receptor antagonist e.g., ondansetron
  • Antipsychotic e.g., pimozide
  • SSRl e.g., Pruritic psychiatric disorders (e.g., neurotic fluvoxamine) excoriation
  • the invention also encompasses the use of serlopitant as a sleep aid. Accordingly, the invention provides a method of aiding sleep, comprising administering to a subject suffering from a sleep problem or disorder an effective amount of serlopitant or a pharmaceutically acceptable salt, solvate or polymorph thereof. An additional sleep-aiding agent optionally can also be administered to the subject.
  • Serlopitant can aid sleep in subjects who suffer from a sleep disorder or a sleep problem in general.
  • serlopitant may have a sedative effect (reducing irritability, anxiety or excitement) and/or a hypnotic effect (inducing, sustaining and/or lengthening sleep).
  • sleep disorders examples include without limitation insomnia (including primary and secondary insomnia, and transient, acute and chronic insomnia); sleeping sickness (African trypanosomiasis); circadian rhythm sleep disorders (e.g., advanced sleep phase disorder [ASPD], delayed sleep phase disorder [DSPD], irregular sleep wake rhythm, non-24 hour sleep-wake disorder, jet lag and shift work sleep disorder [SWSD]); parasomnias (e.g., bruxism, rapid eye movement sleep behavior disorder [ BD], periodic limb movement disorder [PL D or nocturnal myoclonus], restless legs syndrome [RLS], sleep paralysis, exploding head syndrome, sleep terror [night terror or Pavor nocturnus], nocturia, nocturnal eating syndrome, sleep talking [somniloquy], sleepwalking [somnambulism] and somniphobia); and breathing-related sleep disorders (e.g., sleep apnea [including central, obstructive and mixed sleep apne
  • sleep apnea including central,
  • serlopitant is administered when the subject desires to sleep (e.g., at night or around bedtime).
  • An effective amount of serlopitant is administered to aid sleep.
  • the effective amount may depend on various factors, including the mode of administration; the age, body weight, general health, sex and diet of the subject; the severity of the sleep problem; and the response of the subject to the treatment.
  • the dose of serlopitant as a sleep aid is about 0.1- 500 mg, or about 0.25-400 mg, or about 0.5-300 mg, or about 1-200 mg, or about 2.5-100 mg, or about 5-50 mg, or as deemed appropriate by the treating physician.
  • a single dose or multiple doses of serlopitant can be administered to aid sleep.
  • the dosage of serlopitant to aid sleep is about 0.01- 10 mg/kg, 0.025- 7.5 mg/kg, 0.05-5 mg/kg, 0.075-2.5 mg/kg or 0.1-1 mg/kg body weight, or as deemed appropriate by the treating physician.
  • Serlopitant can be administered via any suitable route.
  • Potential routes of administration of serlopitant include without limitation oral, parenteral (including intramuscular, subcutaneous, intradermal, intravenous, intraarterial, intramedullary and intrathecal), intraperitoneal, and topical (including dermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], intraocular [e.g., by eye drop], pulmonary [e.g., by inhalation], buccal, sublingual, rectal and vaginal).
  • serlopitant is administered orally.
  • serlopitant is administered topically via a buccal or sublingual tablet or pill.
  • the buccal or sublingual tablet or pill can be designed to provide faster release of serlopitant for more rapid uptake of it into systemic circulation.
  • the buccal or sublingual tablet or pill can contain suitable excipients, including without limitation any combination of fillers and diluents (e.g., mannitol and sorbitol), binding agents (e.g., sodium carbonate), wetting agents (e.g., sodium carbonate), disintegrants (e.g., crospovidone and croscarmellose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium stearyl fumarate), stabilizers (e.g., sodium bicarbonate), flavoring agents (e.g., spearmint flavor), sweetening agents (e.g., sucralose), and coloring agents (e.g.,
  • an (one or more) additional sleep-aiding agent is administered in combination with serlopitant to aid sleep.
  • the additional sleep-aiding agent can be administered concurrently with or sequentially to (before or after) administration of serlopitant. If administered concurrently with serlopitant, the additional sleep-aiding agent can be contained in the same
  • composition as serlopitant or in separate compositions.
  • Use of serlopitant may reduce the dosage of and/or the length of treatment with the additional sleep-aiding agent which would otherwise be required and thereby minimize or avoid any adverse effects (e.g., dependence or addiction) of the additional sleep-aiding agent.
  • the additional sleep-aiding agent can be selected for its soporific property or for its ability to treat the sleep disorder or the underlying cause of the sleep disorder (e.g., stress, anxiety, depression or a neurological condition).
  • the additional sleep-aiding agent is selected from the group consisting of hypnotics, sedatives, anxiolytics, antipsychotics and antidepressants.
  • a particular sleep-aiding agent can have pharmacological effects that fall in multiple categories (e.g., benzodiazepines can have a sedative or anxiolytic effect at a lower dose and a hypnotic effect at a higher dose).
  • the additional sleep-aiding agent is selected from the group consisting of:
  • antidepressants including tricyclic antidepressants (e.g., amitriptyline, amitriptylinoxide, amoxapine, clomipramine, desipramine, dosulepin [dothiepin], doxepin, imipramine, lofepramine, melitracen, nortriptyline, protriptyline and trimipramine), tetracyclic antidepressants (e.g., amoxapine, maprotiline, mazindol, mianserin, mirtazapine and setiptiline), selective serotonin reuptake inhibitors (SSRIs, e.g., citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline), serotonin antagonist and reuptake inhibitors (SARIs, e.g., etoperidone, lorpiprazole, lub
  • thioxanthenes e.g., clopenthixol, zuclopenthixol, flupentixol and thiotixenej
  • second-generation (or atypical) antipsychotics e.g., amisulpride, aripiprazole, asenapine, clozapine, iloperidone, loxapine, amoxapine, lurasidone, olanzapine, quetiapine, norquetiapine, risperidone, paliperidone, sertindole, trimipramine, ziprasidone and zotepine), and analogs and derivatives thereof; antihistamines that inhibit action at the histamine H-i receptor, including first-generation antihistamines such as alimemazine (trimeprazine), antazoline, azatadine, bromazine, carbinoxamine, chlorpromaz
  • pheniramine brompheniramine, chlorpheniramine, fluorpheniramine, orphenadrine, phenyltoloxamine, promethazine, tripelennamine and triprolidine, and analogs and derivatives thereof;
  • GABA gamma-aminobutyric acid
  • non-benzodiazepines also called Z-drugs
  • Z-drugs that are positive allosteric modulators of the GABA A receptor
  • beta-carbolines e.g., abecarnil, gedocarnil and ZK-93423
  • cyclopyrrolones e.g., pagoclone, pazinaclone, suproclone, suriclone, zopiclone and eszopiclone
  • imidazopyridines e.g., alpidem, necopidem, saripidem and Zolpidem
  • pyrazolopyrimidines e.g., divaplon, fasiplon, indiplon, lorediplon, ocinaplon, panadiplon, taniplon and zaleplon
  • triazolopyridazines e.g., CL-218,872
  • barbiturates that are positive allosteric modulators of the GABA A receptor, such as allobarbital, amobarbital, aprobarbital, alphenal, barbital, brallobarbital, butabarbital, mephobarbital, pentobarbital, phenobarbital, secobarbital and sodium thiopental, and analogs and derivatives thereof;
  • GABA analogs such as gabapentin and pregabalin, and analogs and derivatives thereof;
  • melatonin receptor e.g., ⁇ and/or MT 2
  • melatonin receptor e.g., ⁇ and/or MT 2
  • agonists such as melatonin, agomelatine, LY- 156,735, piromelatine, ramelteon and tasimelteon, and analogs and derivatives thereof;
  • orexin receptor e.g., OX
  • orexin receptor antagonists such as almorexant, suvorexant, SB- 334,867, SB-408,124, SB-649,868, TCS-OX2-29, and N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2- sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA), and analogs and derivatives thereof;
  • 4-quinazolinones such as afloqualone, cloroqualone, diproqualone, etaqualone, mebroqualone, mecloqualone, methaqualone, methylmethaqualone and nitromethaqualone, and analogs and derivatives thereof;
  • opioids e.g., for pain-associated sleep disorders
  • opioids such as buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, methadone, morphine, ethylmorphine, oxycodone, oxymorphone, pethidine, propoxyphene, dextropropoxyphene, thebaine and tramadol, and analogs and derivatives thereof;
  • Cannabis including cannabinoids such as cannabidiol fCBD] and
  • tetrahydrocannabinol THC
  • Duboisia hopwoodii pituri
  • Humuius lupulus hops
  • Hypericum perforatum St. John's wort
  • Lactuca virosa opium lettuce
  • Lavandula lavender
  • Matricaria chamomilla chamomile
  • Nepeta cataria catnip
  • Passiflora passion flowers
  • P incamata Piper methysticum
  • Prostanthera striatiflora striped mintbush
  • Sceletium tortuosum kanna
  • Scutellaria e.g., S. canescens, S. cordifolia, S. galericulata and S. lateriflora
  • Valeriana officinalis valerian
  • Withania somnifera ashwagandha
  • S-adenosyl-L-homocysteine L-tryptophan, L-arginine-L- aspartate, delta sleep-inducing peptide (DSIP), chloral hydrate, ethanol, 2-methyl-2-butanol, gamma- hydroxybutyric acid (GHB), glutethimide, medetomidine, dexmedetomidine, menthyl isovalerate (validol), S32212, a 2 adrenergic agonists (e.g., clonidine), and carbonic anhydrase inhibitors (e.g., acetazolamide and topiramate), and analogs and derivatives thereof.
  • DSIP delta sleep-inducing peptide
  • chloral hydrate ethanol
  • 2-methyl-2-butanol 2-methyl-2-butanol
  • GLB gamma- hydroxybutyric acid
  • glutethimide medetomidine
  • dexmedetomidine de
  • the additional sleep-aiding agent can also be selected for its ability to treat a condition that contributes to sleep difficulty (e.g., abnormal bodily movement or behavior).
  • a condition that contributes to sleep difficulty e.g., abnormal bodily movement or behavior
  • an anticonvulsant can be used in combination with serlopitant to treat a parasomnia, such as restless legs syndrome, periodic limb movement disorder or nocturnal eating syndrome. Examples of
  • anticonvulsants include without limitation carbamazepine, gabapentin, pregabalin, valproic acid and salts thereof (e.g., sodium valproate), and analogs and derivatives thereof.
  • the additional sleep-aiding agent can be administered via any suitable mode.
  • the additional sleep-aiding agent is administered orally, bucally or sublingual ⁇ .
  • administering a should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individuals body in a therapeutically useful form and therapeutically effective amount, including, but not limited to, oral dosage forms, such as tablets, capsules, syrups,
  • the terms “treat”, “treating” and “treatment” of chronic pruritus all refer to reducing the frequency of symptoms of acute or chronic pruritus (including eliminating them entirely), avoiding the occurrence of acute or chronic pruritus and/or reducing the severity of symptoms of acute or chronic pruritus.
  • the term “therapeutically effective amount” refers to a sufficient quantity of the compounds of the present invention, in a suitable composition, and in a suitable dosage form to treat the noted disease conditions. The “therapeutically effective amount” will vary depending on the compound, the severity of the condition causing the pruritus, and the age, weight, etc., of the patient to be treated.
  • loading dose refers to the amount of the compounds or compositions of the present invention that is often larger than subsequent doses, administered for the purpose of establishing a therapeutic level of the drug. More generally, a loading dose is the amount of Compound I, or a pharmaceutically acceptable salt, solvate or polymorph thereof, administered to a patient with pruritus given sometime after presentation but before initiation of one or more maintenance doses.
  • a loading dose refers to one or a series of doses that may be given at the onset of therapy to achieve a target concentration of an active ingredient quickly.
  • the present methods for treatment of pruritus require administration of seriopitant, or a pharmaceutical composition containing seriopitant, to a patient in need of such treatment.
  • the compound and/or pharmaceutical compositions are preferably administered orally.
  • Various delivery systems are known, (e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc.) can be used to administer a seriopitant compound and/or composition.
  • the compound and/or pharmaceutical compositions may be delivered via sustained release dosage forms.
  • the amount of seriopitant, a pharmaceutically acceptable salt, solvate or polymorph thereof, that will be effective in the treatment pruritus in a patient will depend on the specific nature of the condition, and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The specific dose level for any particular individual will depend upon a variety of factors including the activity of the composition, the age, body weight, general physical and mental health, genetic factors, environmental influences, sex, diet, time of administration, route of administration, rate of excretion, and the severity of the pruritus being treated.
  • the dosage forms are adapted to be administered to a patient three, two or one time a day. More preferably, a therapeutically effective amount is taken once per day. Alternatively, a dose may be taken every other day, every third day, every fourth day or once a week. In some
  • seriopitant is administered under a chronic dosing regimen.
  • a therapeutically effective amount of seriopitant is administered over a period of at least 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months or longer.
  • Doses may be taken at any time convenient to the patient. However, to minimize side effects such as dizziness or drowsiness, a daily dose may be taken at bedtime.
  • NK-1 receptor antagonists have been shown to cause drowsiness in human clinical trials for uses other than treating pruritus. For example, Ratti et al. reported as much as a doubling in the incidence of somnolence vs. placebo in patients treated with casopitant for major depressive disorder (J. Clin. Psychopharmacol., 2011,
  • NK-1 receptor antagonist L- 759274 as an anti-depressant ( . S. Kramer er al., Neuropsychopharm., 2004, 29:385-392).
  • serlopitant is administered before the patient goes to bed.
  • Dosing may be provided alone or in combination with other drugs and may continue as long as required for effective treatment pruritus.
  • the compounds of the present invention may be administered in combination with another substance that has a complimentary effect to the tachykinin and substance P inhibitory effect of the present invention.
  • NK-1 receptor antagonists such as, but not limited to, casopitant (GW679769), L-759274, L-733060, CP122J21, BIIF 1149CL, DNK333, 516102, ezlopitant, rolapitant, orvepitant, LY-686017, lanepitant (LY-303870), maropitant, vestipitant, vofopitant, aprepitant, fosaprepitant, AV-818, and TA-5538.
  • casopitant GW679769
  • L-759274 L-733060
  • CP122J21 BIIF 1149CL
  • DNK333 ezlopitant
  • rolapitant rolapitant
  • orvepitant LY-686017
  • lanepitant LY-303870
  • maropitant vestipitant
  • vofopitant vofopitant
  • aprepitant fosaprepitant
  • AV-818 TA-5538.
  • Dosage ranges of compounds of the present invention for oral administration may be stated in terms of amount of drug administered per time period.
  • a certain amount of active ingredient may be given one or more times a day as appropriate according to the factors described above. For example, doses may be taken once a day, twice a day, three times a day, four times a day, or more.
  • Suitable dosages range from about 0.1 mg to about 30 mg, and preferably, from about 1 mg to about 7.5 mg.
  • Suitable dosages are typically 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 100 mg or 200 mg one or more times a day.
  • a dose of 0.25 mg, 1 mg or 5 mg is administered once a day.
  • suitable dosage ranges of compounds of the present invention for oral administration are generally about 0.001 mg to about 500 mg of drug per kilogram body weight, preferably from about 0.1 mg to about 200 mg of drug per kilogram body weight, and more preferably about 1 to about 100 mg/kg-body wt. per day. Dosage ranges may be readily determined by methods known to the skilled artisan. The amount of active ingredient that may be, for instance, combined with carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. Dosage unit forms will generally contain between about 0.25 mg to about 500 mg of active ingredient.
  • a dosing schedule is used where a loading dose is administered, followed by either (i) a second loading dose, or doses, and a maintenance dose (or doses), or (ii) a maintenance dose or doses, without a second loading dose, as determined to be appropriate by one skilled in the art.
  • the schedule for administration of the loading and maintenance doses may be determined based upon the individual requirements of a particular patient.
  • one loading dose is administered, followed by administration of a therapeutically effective maintenance dose after an appropriate interval, such as after one day.
  • a loading dose is administered on day 1, a second loading dose on day 2, and the maintenance dose is administered on day 3 and thereafter for the duration of therapy.
  • the loading dose may be five, four, three or two times the maintenance dose.
  • the loading dose is three times the maintenance dose.
  • the active drug can be administered via any suitable mode (e.g., orally).
  • compositions of the present invention can be tested in experimental animal models of pruritus known to those skilled in the art.
  • various mouse models have been utilized to evaluate treatments for itching.
  • Tsukumo et al. describe a model in which 4- ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone) induces chronic dermatitis with an associated itch response in BALB/c mice that can be used to determine whether an anti-pruritic treatment is effective (J. Pharmacol. Sci., 2010, 113:255-262).
  • Costa et al. report a similar model in which
  • Phoneutria nigriventer spider venom is used as the itch inducer (Vascul. Pharmacol., 2006, 45(4):209- 14).
  • Ohmura ef al. use picrylchloride in NC/Nga mice to stimulate scratching behavior ⁇ Eur. J. Pharmacol., 2004; 491:191-194).
  • itching is induced in the subject animal with an irritating agent, the test compound or a placebo is administered, and the animal observed under controlled conditions. Scratching behavior is quantified and analyzed using standard statistical techniques. A test compound is considered effective if either continuous or severe scratching is suppressed.
  • the efficacy of the methods and compositions of the present invention in the treatment of acute and chronic pruritus can also optionally be evaluated in human clinical trials conducted under appropriate standards and ethical guidelines as set forth by the U.S. Food and Drug Administration (FDA).
  • FDA Food and Drug Administration
  • Phase II trials assessing the safety and efficacy of the drug in patients with the condition being treated are conducted. Typically, such trials are double-blinded and placebo-controlled, and may be dose-ranging.
  • Phase ill studies gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
  • VAS Visual Analog Scale
  • the patient is asked to draw a vertical line to indicate the horizontal scale at a point that corresponded to the intensity of the symptom.
  • the length from the left end to the vertical mark made by the patient is measured in millimeters. Separation in one-hundredths is regarded as sufficiently sensitive (R. C. Aitken, Proc. R. Soc. Med, 1969, 62:989-993).
  • the results may be analyzed using standard statistical techniques known to those skilled in the art.
  • the Dermatology Life Quality Index may be used to evaluate the efficacy of a chronic pruritus treatment.
  • the DLQI a self-administered general dermatology quality of life questionnaire, was originally developed and published in a dermatology clinic at University Hospital of Wales (A. Y. Finlay and G. K. Khan, Clin. Exper. Derm., 1994,19:210-216). Independent studies have verified that the DLQI is an easy and efficient method for assessing quality of life in dermatology patients (H. B. Hahn ef a/., J. Am. Acad. Dermatol., 2001, 45(1):44-8).
  • a current version of the simple, ten-question validated questionnaire, with instructions for use and scoring is available from the School of Medicine, Cambridge University, Wales, UK (world wide web URL dermatology.org.uk/quality/).
  • Tablet potencies of 0.25, 1 and 5 mg are prepared as a compressed tablet formulation.
  • the tablet manufacturing process is the same for all proposed potencies. The process consists of the following steps: 1) Compound 1, mannitol and sodium lauryl sulfate are blended; 2) the remaining mannitol is added to the blender and mixed; 3) microcrystalline cellulose, croscarmellose sodium, and colloidal silica are added to the blender containing the mixture above to complete the mixing and the blend is de-agglomerated if necessary; 4) the blend is lubricated with magnesium stearate which has been previously screened, if necessary; 5) the lubricated blend is roller compacted and milled, and then lubricated with magnesium stearate, which has been previously screened, if necessary; and 6) the mixture is then compressed into tablets of the appropriate weight.
  • [00124J Serlopitant (Compound 1) may also be supplied to the clinic as liquid-filled capsules.
  • Table 2 shows the qualitative/quantitative composition of exemplary dosages. Minor variations in the excipient quantities (+/-10 %) may occur during the drug development process.
  • Capsules are provided by Capsugel (Morristown, J) and contain gelatin and titanium dioxide
  • the formulation is prepared by dissolving the drug substance in mono- and di-glycerides. Furthermore, 0.1 wt% butylated hydroxyanisole is added as an antioxidant. Initial capsule strengths are dispensed into hard gelatin capsules and sealed by spraying with a 1 :1 (wt/wt) water: ethanol solution. Subsequent potencies including 0.25, 1, and 4 mg are dispensed into hard gelatin capsules and sealed with a band of gelatin/polysorbate 80. Corresponding placebo formulations are prepared in a similar manner, but without the addition of the drug substance and the antioxidant.
  • the capsule manufacturing process is the same for all potencies.
  • the process consists of the following steps: 1) the mono- and di-glycerides excipient is melted at 40°C, if necessary; 2) the mono- and diglycerides are added to an appropriately sized, jacketed vessel and mixing is initiated; 3) the butylated hydroxyanisole is added to the mono- and di-glycerides and mixed until dissolved
  • a well-controlled human clinical trial testing the efficacy of three dosages of serlopitant in the treatment of chronic pruritus is conducted in accordance with the ICH Guidelines for Good Clinical Practices, the U.S. Code of Federal Regulations, the Health Insurance Portability and Accountability Act (HIPAA), and any local regulatory requirements.
  • the study is a Phase II randomized, double-blind, parallel group, placebo-controlled, multicenter trial designed to test the efficacy and safety of several doses of serlopitant versus placebo in patients with chronic pruritus.
  • the study patient population includes adult, males or females, 18 to 72 years of age.
  • the patients must be previously diagnosed with chronic pruritus caused by any etiology, except uremia, hepatic failure, cancer or cancer therapy, with chronic pruritus defined as greater than 6 weeks of itching and a VAS score of greater than 7.
  • Patients are randomized to receive either placebo or one of three doses of active agent. Patients take active drug or placebo once daily by mouth for a total of 2 to 8 weeks.
  • the maximum study duration for each subject is approximately 14 weeks and includes a screening period of up to 2 weeks, a treatment period of 2-8 weeks, and a follow-up period of up to 4 weeks.
  • the study parameters are summarized in Table 3.
  • Additional clinical trials according to a similar design may be conducted to test different dosage levels of the active ingredient or to differentiate between optimal doses or dosing schedules. Further, the efficacy of the drug in specific populations, such as the elderly, children, or patients with uremia, hepatic failure, cancer or patients undergoing cancer therapy, may be determined in additional clinical trials conducted in a similar fashion.
  • Table 5 shows various topical formulations containing serlopitant.
  • the formulations contain VanicreamTM Moisturizing Skin Cream (“VM”), VanicreamTM Lite Lotion (“VLL”) or Aquaphor® healing Ointment ("AP", from Eucerin) as the base or carrier.
  • VM and VLL are oil-in-water emulsion and AP has an oil base.
  • a stock solution of free base serlopitant (Compound 1, or "Cpd 1") in ethanol (EtOH) was prepared by dissolving free base serlopitant in ethanol to the maximum extent and then filtering the resulting solution through an Anotop® 25 inorganic filter having a 0.02 micron pore size.
  • Free base serlopitant has a maximum solubility in ethanol of 64.5 mg/g EtOH, or 6.45% w w.
  • the stock solution of serlopitant/ethanol was added to a tared tube containing a particular amount of the base until the resulting mixture weighed 25.0 g. The mixture was mixed vigorously for 2 minutes using a vibration stand and then was rotated slowly for 4 days.
  • ethanol containing no serlopitant was added so that the "B" and "C” formulations would contain the same amount of base and ethanol.
  • AP was determined to be an unsuitable base for an ethanol solution containing serlopitant because of ethanol insolubility in that base.
  • the VM base appeared stable/unchanged under 15x microscopic magnification after 4 days of mixing with 15.5% ethanol.
  • the VLL base showed some aggregation of lamellar structures under 15x microscopic magnification after 4 days of mixing with 15.5% ethanol, but the overall change to the base appeared minor.
  • the VM and VLL formulations can be tested, e.g., for the skin permeation of serlopitant.
  • Topical formulations A-D used in the in vitro skin permeation studies are shown in Table 6.
  • the bases “VM” and “VLL” of formulations A-D are described in Example 4.
  • Formulations A-D were prepared according to the procedures described in Example 4.
  • FIG. 2 illustrates a Franz diffusion cell.
  • a Franz diffusion cell having a circular permeation area of 4.15 cm 2 and a receptor chamber volume of 19 mL was set up with a thermo- regulated outer water jacket to maintain the temperature at 37 °C.
  • the receptor chamber was filled with 19 mL 1*PBS (pH 7.5) containing 10% ethanol and 1% Tween® 80. Solubility test indicated that serlopitant remained soluble at concentrations of 0.5, 5 and 50 ug/mL in this solution after 1 hour of incubation at 37 °C. The solubility of serlopitant decreased significantly if Tween® 80 was not used and decreased slightly if ethanol was not used.
  • a Strata-X 33 urn Polymeric Reverse-Phase column with 30 mg sorbent mass /1 mL volume (Phenomenex) was conditioned with 1 mL of methanol and equilibrated with 1 mL of water. 300 uL of sample was loaded to the column followed by a wash with 1 mL of 30% methanol. Serlopitant was eluted with 2% formic acid in acetonitrile. The sample then was concentrated by blow drying with nitrogen and re-suspended in 50 uL of 50% methanol. A working standard was first generated by spiking the diffusion buffer with known concentrations of serlopitant, which was then processed using the same SPE method.
  • FIG. 3 shows the cumulative release of serlopitant from topical formulations B and C into the receptor chamber at 0.5, 1, 2, 4, 6, 18 and 22 hours. After an initial lag, serlopitant was detected by LC-MS/MS in the receptor chamber at 6 hours.
  • FIG. 3 indicates that topical formulation B resulted in greater penetration of serlopitant through the skin than topical formulation C in this in vitro study.
  • the amount of serlopitant retained in the skin was determined at the end of the experiment.
  • the skin was wiped and washed with methanol.
  • the formulation-treated area was cut into horizontal sections of 25 urn using a cryostat. Every 10 sections were pooled, placed in Eppendorf tubes, weighed and digested with twice the volume of 1 mg/mL liberase at 37 °C for 1 hour. Digested skin sections were further homogenized with a probe sonicator. To 25 uL of the skin homogenate were added 25 uL of 50% methanol and 00 uL of acetonitrile/methanol to extract serlopitant.
  • FIG. 4 shows the amount of serlopitant (called "VPD737" in FIG. 4) retained in the skin at the end of the experiment.
  • Each bar represents ug of serlopitant/g of skin in 250 urn skin layers.
  • the bars from left to right represent the amount of serlopitant retained in skin layers from the stratum corneum to the dermis.
  • Table 7 provides non-limiting examples of topical formulations that can be prepared with serlopitant or a salt, solvate or polymorph thereof, and optionally an additional therapeutic agent.
  • ointment propylene glycol mineral oil, petrolatum, steareth-2, tocopherol, EDTA or
  • ointment propylene glycol fatty alcohol citrate, fatty acid pentaerythritol ester, sorbitan
  • sesquioleate white petrolatum, beeswax, aluminum stearate, butylated hydroxyanisole (BHA), citric acid, and optionally water
  • ointment an alcohol (e.g., ethanol and/or propylene glycol), polyethylene or white
  • gel glycerol carbomer 940, poloxamer, dimethicone, disodium lauryl sulfosuccinate, silicon dioxide, a preservative (e.g., benzoyl peroxide and/or methyl paraben), EDTA or disodium edetate, a pH adjuster (e.g., NaOH or lactic acid), and water gel glycerol, hydroxy-beta-cyclodextrin, hydroxyethyl cellulose, parabens, EDTA or disodium edetate, and water
  • polysorbate 80 e.g., polysorbate 80, a preservative (e.g., benzoic acid), EDTA or disodium edetate, a pH adjuster (e.g., NaOH or lactic acid), and water
  • gel propylene glycol Carbopol® 941 , PEG 400, methyl paraben, a pH adjuster (e.g., NaOH or lactic acid), and water
  • adjuster e.g., NaOH or lactic acid
  • sulfosuccinate e.g., benzoyl peroxide
  • a pH adjuster e.g., NaOH or lactic acid
  • gel glycerol propylene glycol, aloe vera gel, diazolidinyl urea, capryl/capramidopropyl betaine, parabens, citric acid, sodium citrate, and water
  • cyclomethicone light mineral oil, steareth-21, benzyl alcohol, sorbic acid or potassium sorbate, a pH adjuster (e.g., NaOH or lactic acid), and water lotion isopropanol, propylene glycol, hydroxypropyl cellulose, sodium phosphate
  • a pH adjuster e.g., NaOH or citric acid
  • glycerol e.g., cetostearyl alcohol, isostearyl alcohol, stearic acid, glyceryl stearate,
  • suppoan alcohol e.g., ethanol and/or propylene glycol
  • glycerides of saturated fatty sitory acids e.g., ethanol and/or propylene glycol
  • (nasal) 80 disodium edetate, potassium sorbate, a pH adjuster (e.g., HCI), water, and
  • an alcohol e.g., ethanol
  • (nasal) 80 benzalkonium chloride, phenylethyl alcohol, water, and optionally an alcohol

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Abstract

L'invention concerne des procédés pour traiter le prurit avec des antagonistes du récepteur NK -1 tel que le serlopitant. L'invention concerne également des compositions pharmaceutiques comprenant des antagonistes du récepteur NK -1 tel que le serlopitant. De plus, l'invention concerne le traitement d'un trouble associé à un prurit avec du serlopitant et un autre agent antiprurigineux, et l'utilisation du serlopitant en tant qu'agent favorisant le sommeil, éventuellement en combinaison avec un autre agent favorisant le sommeil.
EP14744671.0A 2013-06-24 2014-06-24 Utilisation de serlopitant, antagoniste du récepteur nk -1, dans le traitement du prurit Withdrawn EP3013336A1 (fr)

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US201361838784P 2013-06-24 2013-06-24
US13/925,509 US8906951B1 (en) 2013-06-24 2013-06-24 Use of NK-1 receptor antagonists in pruritus
PCT/US2014/043811 WO2014209962A1 (fr) 2013-06-24 2014-06-24 Utilisation de serlopitant, antagoniste du récepteur nk -1, dans le traitement du prurit

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US9198898B2 (en) 2013-06-24 2015-12-01 Tigercat Pharma, Inc. Use of NK-1 receptor antagonists in pruritus
CN106852118A (zh) 2014-09-19 2017-06-13 赫伦治疗有限公司 阿瑞吡坦乳剂制剂
AU2016226006B2 (en) 2015-03-04 2021-03-04 Vanda Pharmaceuticals Inc. Method of treatment with tradipitant
US9974742B2 (en) 2016-02-01 2018-05-22 Heron Therapeutics, Inc. Emulsion formulations of an NK-1 receptor antagonist and uses thereof
AU2016391046A1 (en) * 2016-02-01 2018-08-16 Heron Therapeutics, Inc. Emulsion comprising an NK-1 receptor antagonist
EP3478283A4 (fr) * 2016-06-29 2020-07-22 Menlo Therapeutics Inc. Utilisation d'antagonistes de neurokinine-1 dans le traitement d'une variété d'états pruritiques
BR112020004964A2 (pt) * 2017-09-13 2020-09-15 Vanda Pharmaceuticals Inc. método que consiste em administrar uma quantidade de tradipitant eficaz, aperfeiçoamento, método aperfeiçoado para tratar um paciente que sofre de prurido ou dermatite atópica com tradipitant, e, métodos para tratar um paciente com prurido ou dermatite atópica, para selecionar e para determinar uma dosagem de tradipitant eficaz, para determinar que um paciente tem probabilidade de responder ao tratamento de dermatite atópica com tradipitant e para identificar um paciente.
CN111886025A (zh) * 2017-11-01 2020-11-03 新加坡国立大学 血清素能药物治疗病毒诱发的血小板减少症的用途
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JP2016523260A (ja) 2016-08-08
BR112015031724A2 (pt) 2017-07-25
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