WO2012019204A2 - Agent thérapeutique pour administration intranasale et son procédé de fabrication et d'utilisation - Google Patents

Agent thérapeutique pour administration intranasale et son procédé de fabrication et d'utilisation Download PDF

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Publication number
WO2012019204A2
WO2012019204A2 PCT/US2011/051981 US2011051981W WO2012019204A2 WO 2012019204 A2 WO2012019204 A2 WO 2012019204A2 US 2011051981 W US2011051981 W US 2011051981W WO 2012019204 A2 WO2012019204 A2 WO 2012019204A2
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WIPO (PCT)
Prior art keywords
rhinitis
composition
concentration
capsicum
allergic
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PCT/US2011/051981
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English (en)
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WO2012019204A3 (fr
Inventor
Wayne Jeffrey Perry
Lynne M. Millheiser
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Dynova Laboratories, Inc.
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Publication date
Priority claimed from US12/849,088 external-priority patent/US20100322961A1/en
Application filed by Dynova Laboratories, Inc. filed Critical Dynova Laboratories, Inc.
Publication of WO2012019204A2 publication Critical patent/WO2012019204A2/fr
Publication of WO2012019204A3 publication Critical patent/WO2012019204A3/fr

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K9/0043—Nose

Definitions

  • the present invention relates to a therapeutic agent capable of intranasal administration comprising capsicum and/or capsaicinoids as the therapeutic agent.
  • Non-allergic rhinitis affects millions of Americans, but the mechanism(s) remains unknown.
  • Transient receptor potential vanilloid-1 (“TRPV1 ”) may be involved, as single dose studies of intranasal capsaicin, a TRPV1 agonist, have demonstrated reduced nasal congestion in rhinitis subjects.
  • Chronic rhinitis is defined as persistent inflammation of the mucosal membranes lining the nasal cavity, characterized by symptoms of nasal congestion, rhinorrhea, sneezing and itching with or without post-nasal drainage.
  • Settipane RA Lieberman P. Update on nonallergic rhinitis. Ann Allergy Asthma Immunol 2001 ; 86:494-507; quiz -8. Wallace DV, Dykewicz MS, Bernstein Dl, Blessing-Moore J, Cox L, Khan DA, et al. The diagnosis and management of rhinitis: an updated practice parameter.
  • rhinitis can be divided into inflammatory and non-inflammatory rhinitis.
  • Wallace DV Dykewicz MS, Bernstein Dl, Blessing-Moore J, Cox L, Khan DA, et al. The diagnosis and management of rhinitis: an updated practice parameter.
  • Inflammatory rhinitis includes seasonal or perennial allergic rhinitis, entopic rhinitis and non-allergic rhinitis eosinophilic syndrome
  • non-inflammatory rhinitis includes vasomotor rhinitis (“VMR”), commonly referred to as idiopathic rhinitis, and other non-allergic rhinitis conditions such as rhinitis medicamentosa, gustatory rhinitis and hormonally-induced rhinitis.
  • VMR vasomotor rhinitis
  • TRP transient receptor protein
  • Ipratropium bromide nasal spray in non-allergic rhinitis efficacy, nasal cytological response and patient evaluation on quality of life. Clin Exp Allergy 1994; 24:1049-55. Lieberman PL, Settipane RA. Azelastine nasal spray: a review of pharmacology and clinical efficacy in allergic and nonallergic rhinitis. Allergy Asthma Proc 2003; 24:95-105. Scadding GK, Lund VJ, Jacques LA, Richards DH. A placebo-controlled study of fluticasone propionate aqueous nasal spray and beclomethasone dipropionate in perennial rhinitis: efficacy in allergic and non-allergic perennial rhinitis.
  • Capsaicin is a pungent substance found in capsicum spp. (red pepper) that is known to ablate sensory nerve fibers in NAR patients leading investigators to postulate a role for afferent C-fibers in NAR. (Blom HM, Van Rijswijk JB, Garrelds IM, Mulder PG, Timmermans T, Gerth van Wijk R.
  • TRPV1 TRP vanilloid-1
  • Intranasal capsaicin reduces nasal hyperreactivity in idiopathic rhinitis: a double-blind randomized application regimen study. Allergy 2003; 58:754-61 .
  • capsicum/capsaicin present in an effective concentration, that may be self- administered as a mono-therapy by the user. Furthermore, Applicant is not aware of any studies demonstrating clinical efficacy of capsicum/capsaicin at concentrations 10% or less of the dosages used in previous rhinitis clinical trials. What is needed in the industry is a composition comprising capsicum/ capsaicin that may be administered intranasally in an effective concentration, allowing the user to self-administer the composition without the need for the user to visit a physician's office for each treatment.
  • capsicum comprising capsaicinoids, including capsaicin
  • capsaicin may be self-administered by the user and provide relief from symptoms.
  • What is needed in the industry is a composition comprising capsicum/capsaicin that is effective in relieving symptoms, but can be used without causing discomfort to the user or requiring adjunct agents.
  • Applicant is not aware of any prior studies investigating the immediate or short-term relief of symptoms provided by the intranasal administration of capsicum as disclosed in the present application. In addition, Applicant is not aware of any prior studies disclosing that a low homeopathic dilution of capsicum is clinically effective for the treatment of rhinitis.
  • a nasally administered composition that provides a rapid onset of relief for rhinitis subjects.
  • an intranasally administered composition having a rapid onset of action and significant reduction of symptoms, that is an attractive mono-therapy or adjunctive therapy for the management of rhinitis symptoms, including, but not limited to, chronic rhinitis symptoms.
  • an intranasally administered composition having a quick onset of action with an average time to first relief in less than thirty minutes, less than five minutes, and even less than one minute.
  • OTC over the counter
  • An embodiment of the present invention is a composition suitable for intranasal administration to a human in need thereof comprising an effective amount of an aqueous homeopathic dilution of capsicum, wherein the composition is suitable for intranasal administration, wherein
  • the rhinitis is at least one of vasomotor rhinitis, non- allergic rhinitis, allergic rhinitis, mixed rhinitis, allergic rhinitis with a non- allergic component, idiopathic rhinitis or a combination thereof.
  • the rhinitis symptom relieved comprises at least one of nasal congestion, sinus pressure, sinus pain, headache or a combination thereof.
  • the composition does not require the administration of a second agent to enable tolerance of the composition.
  • the composition is self- administered.
  • the homeopathic dilution of capsicum comprises about 0.1 to about 2.0 ppm total capsaicinoids, about 0.3 to about 1 .5 ppm total
  • composition may comprise rosemary extract at a concentration of about
  • the composition may comprise potassium sorbate at a concentration of about 0.05% to about 0.3% w/w.
  • the composition may comprise eucalyptol at a concentration of about 0.07% to about 0.15% w/w.
  • the composition may comprise vegetable glycerin at a concentration of about 3.5% to about 5.0% w/w, or about 3.9% to about 4.5% w/w.
  • the composition may comprise ascorbic acid at a concentration of about 0.10% to about 0.90% w/w.
  • the composition may comprise sea salt at a concentration of about 0.40% to about 1 .2% w/w.
  • An embodiment of the present invention is a composition suitable for intranasal administration to a human in need thereof comprising an effective amount of an aqueous solution of capsicum at a concentration of about 0.00060% to about 0.010% w/w containing about 0.1 to about 2.0 ppm total capsaicinoids, wherein the composition is suitable for intranasal administration, wherein administration of the composition relieves at least one rhinitis symptom in the human in need thereof.
  • the rhinitis is at least one of vasomotor rhinitis, non-allergic rhinitis, allergic rhinitis, mixed rhinitis, allergic rhinitis with a non-allergic component, idiopathic rhinitis or a combination thereof.
  • the rhinitis symptom relieved comprises at least one of nasal congestion, sinus pressure, sinus pain, headache or a combination thereof.
  • the composition does not require the administration of a second agent to enable tolerance of the composition.
  • the composition is self-administered.
  • the composition may comprise an aqueous solution of capsicum at a concentration of about 0.0020% to about 0.0080% w/w containing about 0.3 to about 1 .5 ppm total capsaicinoids, or at a
  • composition may comprise rosemary extract at a concentration of about 0.02% to about 0.25% w/w, at a concentration of about 0.05% to about 0.10% w/w, or at a concentration of about 0.06% to about 0.07% w/w.
  • An embodiment of the present invention is a composition suitable for intranasal administration to a human in need thereof comprising an effective amount of an aqueous solution of capsicum at a concentration of about 0.00060% to about 0.010% w/w containing about 0.1 to about 2.0 ppm total capsaicinoids, rosemary extract at a concentration of about 0.02% to about 0.25% w/w, wherein the composition is suitable for intranasal administration, wherein administration of the composition relieves at least one rhinitis symptom in the human in need thereof.
  • the rhinitis is at least one of vasomotor rhinitis, non-allergic rhinitis, allergic rhinitis, mixed rhinitis, allergic rhinitis with a non-allergic component, idiopathic rhinitis or a combination thereof.
  • the rhinitis symptom relieved comprises at least one of nasal congestion, sinus pressure, sinus pain, headache or a combination thereof.
  • the composition does not require the administration of a second agent to enable tolerance of the composition.
  • the composition is self-administered.
  • the aqueous solution of capsicum may be at a concentration of about 0.0020% to about 0.0080% w/w containing about 0.3 to about 1 .5 ppm total capsaicinoids, or at a concentration of about 0.0030% to about 0.0080% w/w containing about 0.5 to about 1 .5 ppm total capsaicinoids.
  • the composition may comprise rosemary extract at a concentration of about 0.05% to about 0.10% w/w or at a concentration of about 0.06% to about 0.07% w/w.
  • An embodiment of the present invention is a method for the treatment of rhinitis symptoms administered to a human in need thereof comprising the steps of administering intranasally a composition comprising an effective amount of an aqueous homeopathic dilution of capsicum to a human in need thereof, and effecting the relief from at least one rhinitis symptom.
  • the rhinitis is at least one of vasomotor rhinitis, non-allergic rhinitis, allergic rhinitis, mixed rhinitis, allergic rhinitis with a non-allergic component, idiopathic rhinitis or a combination thereof.
  • the rhinitis symptom relieved comprises at least one of nasal congestion, sinus pressure, sinus pain, headache or a combination thereof.
  • the composition does not require the administration of a second agent to enable tolerance of the composition.
  • the composition is self-administered.
  • the capsicum is present in the composition at a concentration of about 0.00060% to about 0.010% w/w containing about 0.1 to about 2.0 ppm total
  • An embodiment of the present invention is a method for the treatment of rhinitis symptoms administered to a human in need thereof comprising the steps of administering intranasally an effective amount of a composition comprising an aqueous homeopathic dilution of capsicum and rosemary extract to a human in need thereof, and effecting the relief from at least one rhinitis symptom.
  • the rhinitis is at least one of vasomotor rhinitis, non-allergic rhinitis, allergic rhinitis, mixed rhinitis, allergic rhinitis with a non- allergic component, idiopathic rhinitis or a combination thereof.
  • the rhinitis symptom relieved comprises at least one of nasal congestion, sinus pressure, sinus pain, headache or a combination thereof.
  • the composition does not require the administration of a second agent to enable tolerance of the composition.
  • the composition is self- administered.
  • the capsicum is present in the composition at a concentration of about 0.00060% to about 0.010% w/w containing about 0.1 to about 2.0 ppm total capsaicinoids.
  • the rosemary extract is present in the composition at a concentration of about 0.02% to about 0.25% w/w.
  • An embodiment of the present invention is a method for the treatment of rhinitis symptoms administered to a human in need thereof comprising the steps of administering intranasally an effective amount of a composition comprising about 0.00060% to about 0.010% w/w capsicum containing about 0.1 to about 2.0 ppm total capsaicinoids and rosemary extract at a concentration of about 0.02% to about 0.25% w/w, and effecting the relief from at least one rhinitis symptom.
  • the rhinitis is at least one of vasomotor rhinitis, non-allergic rhinitis, allergic rhinitis, mixed rhinitis, allergic rhinitis with a non-allergic component, idiopathic rhinitis or a combination thereof.
  • the rhinitis symptom relieved comprises at least one of nasal congestion, sinus pressure, sinus pain, headache or a combination thereof.
  • the composition does not require the administration of a second agent to enable tolerance of the composition.
  • the composition is self-administered.
  • the capsicum may be present in the composition at a concentration of about 0.0020% to about 0.0080% w/w containing about 0.3 to about 1 .5 ppm total capsaicinoids.
  • An embodiment of the present invention is a composition comprising an aqueous homeopathic dilution of capsicum.
  • the homeopathic dilution of capsicum may be at a concentration of about 0.00060% to about 0.010% w/w or containing about 0.1 to about 2.0 ppm total capsaicinoids.
  • the homeopathic dilution of capsicum may be at a concentration of about 0.0020% to about 0.0080% w/w or containing about 0.3 to about 1 .5 ppm total capsaicinoids.
  • the homeopathic dilution of capsicum may be at a composition comprising an aqueous homeopathic dilution of capsicum.
  • the homeopathic dilution of capsicum may be at a concentration of about 0.00060% to about 0.010% w/w or containing about 0.1 to about 2.0 ppm total capsaicinoids.
  • the homeopathic dilution of capsicum may be at a concentration of about 0.0020% to about
  • the composition may comprise rosemary extract at a concentration of about 0.02% to about 0.25% w/w, at a concentration of about 0.05% to about 0.10% w/w, or at a concentration of about 0.06% to about 0.07% w/w.
  • the rhinitis symptoms relieved may comprise at least one of nasal congestion, sinus pressure, sinus pain, headache, or a combination thereof.
  • the composition may comprise eucalyptol at a concentration of about 0.07% to about 0.15% w/w, vegetable glycerin at a concentration of about 3.5% to about 5.0% w/w, vegetable glycerin at a concentration of about 3.9% to about 4.5% w/w, ascorbic acid at a concentration of about 0.10% to about 0.90% w/w, sea salt at a
  • a homeopathic dose of capsicum such as, but not limited to, 5% or less of therapeutic doses known in the art, is still an effective dose.
  • a homeopathic dose of capsicum would still provide a significant benefit as shown in an embodiment of the present invention.
  • a surprising and unexpected result according to an embodiment of the present invention is that the presence of the rosemary extract acts to increase the tolerability of the capsicum in the composition to the user. Applicant is not aware of any disclosure, teaching, or suggestion in the related art that the presence of rosemary extract in a composition containing capsicum would act to make the capsicum more tolerable to the user.
  • An embodiment of the present invention is a composition comprising an aqueous solution of capsicum at a concentration of about 0.00060% to about 0.010% w/w, or containing about 0.1 to about 2.0 ppm total capsaicinoids, including, but not limited to, capsaicin, wherein the composition is suitable for intranasal administration to a human in need thereof.
  • the aqueous solution of capsicum comprises a homeopathic dilution of capsicum.
  • the aqueous solution of capsicum comprises a homeopathic dilution of Capsicum annum.
  • the aqueous solution of capsicum may be at a concentration of about 0.0020% to about 0.0080% w/w, or containing about 0.3 to about 1 .5 ppm total capsaicinoids. In an embodiment the aqueous solution of capsicum may be at a concentration of about 0.0030% to about 0.0080% w/w, or containing about 0.5 to about 1 .5 ppm total capsaicinoids.
  • An embodiment of the present invention is a composition comprising an aqueous solution of capsicum at a concentration of about 0.00060% to about 0.010% w/w.
  • An embodiment may comprise eucalyptol at a concentration of about 0.07% to about 0.15% w/w, wherein the composition is suitable for intranasal administration to a human in need thereof.
  • the eucalyptol may be at a concentration of about 0.13% w/w.
  • the aqueous solution of capsicum comprises a homeopathic dilution of capsicum.
  • the aqueous solution of capsicum may comprise a homeopathic dilution of Capsicum annum. In one
  • the aqueous solution of capsicum may be at a concentration of about 0.0020% to about 0.0080% w/w, or containing about 0.3 to about 1 .5 ppm total capsaicinoids. In one embodiment, the aqueous solution of capsicum may be at a concentration of about 0.0030% to about 0.0080% w/w, or containing about 0.5 to about 1 .5 ppm total capsaicinoids. In an
  • composition may also comprise rosemary extract at a concentration of about 0.02% to about 0.25% w/w, about 0.05% to about 0.10% w/w or comprise rosemary extract at a concentration of about 0.06% to about 0.07% w/w.
  • composition does not require the administration of a separate agent before, during, and/or after administration of the composition to enable tolerance of the composition.
  • composition is self-administered by the human in need thereof.
  • the composition may also comprise vegetable glycerin at a concentration of about 3.5% to about 5.0% w/w or at a concentration of about 3.9% to about 4.5% w/w.
  • the composition may comprise ascorbic acid at a concentration of about 0.10% to about 0.90% w/w, sea salt at a concentration of about 0.40% to about 1 .2% w/w, potassium sorbate at a concentration of about 0.05% to about 0.3%, or a combination thereof.
  • An embodiment of the present invention is a composition comprising an aqueous solution of capsicum at a concentration of about 0.00060% to about 0.010% w/w, or containing about 0.1 to about 2.0 ppm total capsaicinoids and rosemary extract at a concentration of about 0.02% to about 0.25% w/w.
  • An embodiment may further comprise eucalyptol at a concentration of about 0.07% to about 0.15%, vegetable glycerin at a concentration of about 3.5% to about 5.0% w/w or a combination thereof, wherein the composition is suitable for intranasal administration to a human in need thereof.
  • composition may also comprise ascorbic acid at a concentration of about 0.10% to about 0.90% w/w, sea salt at a concentration of about 0.40% to about 1 .2% w/w and potassium sorbate at a concentration of about 0.05 to about 0.3%, or a combination thereof.
  • An embodiment of the present invention is an aqueous solution suitable for intranasal administration to a human in need thereof, comprising an aqueous solution of capsicum at a concentration of about 0.00060% to about 0.010% w/w, or containing about 0.1 to about 2.0 ppm total
  • An embodiment of the present invention is an intranasally administered composition that provides relief from at least one of nasal congestion, sinus pressure, sinus pain and headache with an improved therapeutic response that continues over time with at least one of nasal congestion, sinus pressure, sinus pain and headache significantly improved at about 5, 10, 15, 30 and/or 60 minutes.
  • An advantage of an embodiment of the present invention is an intranasally administered composition having a rapid onset of action and significant reduction of symptoms that may be an attractive mono-therapy or adjunctive therapy for the management of rhinitis symptoms.
  • An embodiment of the present invention is an intranasal composition wherein users experience little to no rebound congestion.
  • An advantage of an embodiment of the present invention is an intranasal composition wherein users experience essentially no alteration, or even an improvement, in olfaction versus placebo after continued use.
  • An advantage of an embodiment of the present invention is a nasally administered
  • composition that provides a rapid onset of relief for rhinitis subjects, while also providing safe, sustained relief over the course of a treatment period.
  • An advantage of an embodiment of the present invention is an intranasally administered composition wherein during a treatment period is significantly effective at improving at least one of nasal congestion, sinus pressure, sinus pain and headache compared to placebo.
  • An advantage of an embodiment of the present invention is an intranasally administered composition that is well-tolerated and with prolonged treatment results in substantially no reduction in olfaction.
  • An advantage of an embodiment of the present invention is an agent that may be used as a mono-therapy comprising capsaicin, dihydrocapsaicin, and nordihydrocapsaicin and other
  • the agent comprises between about 0.000001 % to about 0.01 % by weight of the total water or suspension material weight of capsicum comprising at least, but not limited to, capsaicin, dihydrocapsaicin, and nordihydrocapsaicin, resulting in about 0.0001 to about 1 .5 ppm total capsaicinoids.
  • the agent comprises between about 0.1 ppm to about 2.0 ppm total capsaicinoids comprising at least, but not limited to, capsaicin, dihydrocapsaicin, and nordihydrocapsaicin.
  • the agent comprises capsicum, comprising capsaicin, dihydrocapsaicin, and nordihydrocapsaicin, having a heat range of about 100,000 to about 1 ,000,000 Scoville Heat Units.
  • Capsicum is derived from several Capsicum pepper varieties.
  • the Capsicum variety utilized in embodiments of the present invention is derived from cayenne pepper plants, which may comprise at least one of Capsicum baccatum, Capsicum annum, and Capsicum frutescens, or a combination thereof.
  • the capsicum comprises capsaicin, dihydrocapsaicin, and nordihydrocapsaicin and possibly other capsaicinoids as active ingredients.
  • the capsicum utilized in an embodiment of the present invention may comprise an all natural, water soluble and/or soluble liquid suspension material.
  • the aqueous solution of capsicum may comprise a homeopathic dilution of capsicum.
  • the aqueous solution of capsicum may comprise a homeopathic dilution of Capsicum annum.
  • capsicum comprising capsaicin, dihydrocapsaicin, nordihydrocapsaicin, and possibly other capsaicinoids as opposed to synthetic capsaicin may allow for repeated use and effective delivery without causing an uncomfortable and/or intolerable burning sensation in the nasal mucosa of the user.
  • a combination of at least one synthetic capsaicinoid could also be used.
  • Embodiments of the present invention relate to an agent comprising capsicum comprising capsaicin, dihydrocapsaicin,
  • the aqueous solution of capsicum may comprise a homeopathic dilution of capsicum.
  • the composition may comprise between about 0.000001 % to about 0.008% by weight of the total water or suspension material weight of capsicum comprising capsaicin, dihydrocapsaicin, and nordihydrocapsaicin among others, resulting in about 0.0001 to about 1 .5 ppm total capsaicinoids.
  • the composition comprises between about 0.1 to about 2.0 ppm total capsaicinoids present in capsicum, including, but not limited to, capsaicin, dihydrocapsaicin, and nordihydrocapsaicin.
  • composition may comprise capsicum including capsaicin, dihydrocapsaicin, and
  • the capsicum including, but not limited to, capsaicin, dihydrocapsaicin, and nordihydrocapsaicin is present in a non-caustic and safe amount.
  • the aqueous solution of capsicum comprises a homeopathic dilution of capsicum. In an embodiment the aqueous solution of capsicum comprises a homeopathic dilution of Capsicum annum.
  • An embodiment of the present invention comprises rosemary extract at a concentration of about 0.02% to about 0.50% w/w in addition to the capsicum.
  • the composition may comprise rosemary extract at a concentration of about 0.05% to about 0.10% w/w, or at a concentration of about 0.06% to about 0.07% w/w.
  • a surprising and unexpected result according to an embodiment of the present invention is that the presence of the rosemary extract acts to increase the tolerability of the capsicum in the composition to the user.
  • Applicant is not aware of any disclosure, teaching, or suggestion in the art that the addition of rosemary extract in a composition containing capsicum would act to make the capsicum more tolerable to the user.
  • An embodiment of the present invention may comprise eucalyptol at a concentration of about 0.07% to about 0.15% w/w in addition to the capsicum.
  • An embodiment of the present invention may comprise at least one of vegetable glycerin at a concentration of about 3.5% to about 5.0% w/w, vegetable glycerin at a concentration of about 3.9% to about 4.5% w/w, ascorbic acid at a concentration of about 0.10% to about 0.90% w/w, sea salt at a concentration of about 0.40% to about 1 .2% w/w, potassium sorbate at a concentration of about 0.05% to about 0.30% or a combination thereof, in addition to the capsicum.
  • the composition may be an intranasal spray.
  • the composition may be an intranasal spray wherein the capsicum is released in a metered dose.
  • the composition may be an intranasal spray wherein the capsicum is released in a time released dose.
  • the composition may be disposed in, about and/or around a swab for intranasal delivery.
  • An embodiment of the invention relates to a method of treating a human in need thereof, by delivering the composition described herein and wherein capsicum including, but not limited to, capsaicin, dihydrocapsaicin, and nordihydrocapsaicin is the effective agent.
  • the method comprises the intranasal administration of capsicum comprising, but not limited to, capsaicin, dihydrocapsaicin, and nordihydrocapsaicin effecting the relief of at least one rhinitis symptom.
  • capsicum comprising capsaicinoids, including capsaicin, and possibly other ingredients in Applicant's composition, used for relief of rhinitis and allergic symptoms act via activation of TRP-family receptors.
  • Applicant has developed an in vitro fluorometric assay to measure receptor activity in the presence of various concentrations of capsaicin/ capsaicinoids. The activation of the receptors in the in vitro assay correlates with Applicant's demonstrated symptom relief as evidenced in the examples below.
  • the goal of the in vitro assay is to quantitatively measure TRPV activation to determine the dose response of airway component cells to Applicant's compositions comprising capsaicin/capsaicinoids.
  • TRPV transient receptor protein vanilloid
  • the assay is fluorometric in nature, relying upon a calcium-binding fluor, Fura-4. (available from Invitrogen Life Sciences and other vendors). Fura-4 fluoresces at a specific wavelength when it binds to calcium. Cells are loaded with Fura-4, and under digital confocal observation exposed to capsaicin/capsaicinoid containing compositions. The signal intensity over single cells is captured for 0.5-5 minutes and the result expressed as normalized (to baseline) signal intensity over time. [0052] As shown in Figure 1 , the activation of a calcium channel by the composition will result in an increase in fluorescence.
  • TRPV Transient Receptor Potential V channels
  • concentration at 1 ppm is about 0.0064% w/w capsicum
  • 0.5 ppm concentration is about 0.0032% w/w capsicum
  • 0.25 ppm concentration is about 0.0016% w/w capsicum
  • the 0.10 ppm concentration is about 0.0008% capsicum.
  • the assay demonstrates that there is no calcium uptake in the blank sample (no aromatics, no
  • TRPV1 KO TRPV1 KO
  • capsaicin/capsaicinoid containing formulations is indeed TRPV1 -dependent. Applicant concludes from the data that the capsaicin response is primarily due to TRPV1 , but expects that other TRPs will respond to the aromatics and the affect may be different in different cell types.
  • capsaicin/capsaicinoids that will be effective at relieving rhinitis symptoms in humans in need thereof.
  • Various formulations and concentrations of capsaicin/capsaicinoids have been used by Applicant to successfully treat these symptoms as shown in Examples 2-5 below.
  • the following examples of formulations of compositions wherein the total capsaicinoids provide quick, effective relief from symptoms.
  • the ICX formulation comprises from about 0.00060% to about 0.010% w/w, or comprising about 0.1 to about 2.0 ppm total capsaicinoids, about 0.0020% to about 0.0080% w/w, resulting in about 0.3 to about 1 .5 ppm total capsaicinoids, or preferably about 0.0030% to about 0.0080% w/w, resulting in about 0.5 to about 1 .5 ppm total capsaicinoids.
  • the ICX formulation further comprises rosemary extract at a concentration of about 0.02% to about 0.25% w/w, eucalyptol at a concentration of about 0.07 to about 0.15%, vegetable glycerin at a
  • One embodiment may also comprise potassium sorbate at a concentration of about 0.05% to about 0.30%.
  • One embodiment of the ICX formulation comprises about 0.0064% w/w capsicum, about 0.1 1 % w/w eucalyptol, about 0.067% w/w rosemary extract, about 0.4 to about 0.7% w/w each ascorbic acid and sea salt, about 4.4% w/w vegetable glycerin, in purified water.
  • TNSS total nasal symptom scores
  • Secondary endpoints included changes in individual symptom scores (nasal congestion, sinus pain, sinus pressure, headache, sneezing, rhinorrhea, and post-nasal drainage) over two weeks and average time to first relief.
  • Mean TNSS and individual symptom scores were also recorded after single dosing with ICX vs. placebo at 5, 10, 15, 30 and 60 minute intervals.
  • Rhinitis quality-of-life domains at end of study, and use of rescue medication and safety endpoints were also analyzed. All data was analyzed by the Statistical Analysis System ("SAS"). [0057] Statistically significant differences in changes from baseline to end of study between the ICX and placebo groups were observed for TNSS and each individual symptom (p ⁇ .01 ). The average time to first relief for ICX subjects was 52.6 seconds which was significantly less than placebo (p ⁇ .01 ). For ICX subjects, nasal congestion, sinus pain, sinus pressure and headache were significantly improved at 5, 10, 15, 30, which persisted up until 60 minutes for nasal congestion and sinus pain (p ⁇ .05). No significant difference between groups in adverse events or rescue medication was observed. ICX subjects experienced no rebound congestion and demonstrated an
  • Symptom severity was defined as a morning or evening nasal congestion and/or post nasal drainage score of at least 5 out of 10 on three separate symptom assessments during the 7 day pre-randomization medication wash-out period. This included being symptomatic at least 24 hours prior to and including the day of randomization. Subjects were required to comply with all study related visits and procedures and had to be in generally good health without any uncontrolled chronic health problems.
  • visit two subjects who fulfilled all inclusion/exclusion criteria including the symptom score criteria, were randomized to receive either ICX or filtered water placebo, 1 -2 puffs each nostril, twice daily.
  • subjects were given their first dose of study drug or placebo in the office.
  • subjects clicked the stopwatch when they felt the first onset of symptom relief.
  • Symptom scores and rescue medication requirements consisting of diphenhydramine 25-50 mg up to four times a day (maximum dose 200mg/day), were recorded on subject's home diaries over the three week study period.
  • the primary endpoint was the change in the 12 hour reflective total TNSS recorded by the patient each evening in a daily diary, from baseline to the end of the study (2 weeks).
  • TNSS was a composite score that included nasal congestion, post-nasal drainage, sneezing, rhinorrhea, sinus pain, sinus pressure and headache. These symptoms were chosen based on the "Allergies in America survey" which cited these as the worst symptoms and/or co-morbid conditions experienced by chronic rhinitis patients. (Blaiss MS, Meltzer EO, Derebery MJ, Boyle JM. Patient and healthcare-provider perspectives on the burden of allergic rhinitis.
  • TNSS TNSS, nasal congestion, post-nasal drainage, sneezing, rhinorrhea, sinus pain, sinus pressure and headache
  • Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis.
  • the effect size (ratio of mean difference to TNSS standard deviation) was equal to 0.8.
  • Times to first relief The average time to first relief for ICX was equal to 52.6 seconds (0.8 min), which was significantly lower than the average time of first relief for placebo subjects (p ⁇ .01 ). Eighty percent of subjects receiving ICX experienced first relief in less than one minute compared to 45% of subjects receiving placebo (p ⁇ .05). Symptoms that significantly improved at time to first relief were nasal congestion, sinus pressure and headache (p ⁇ .05) as shown in Table 3.
  • a symptom at first relief was missing, less relief was assumed than was determined from all reported symptom changes at first relief, after adjusting for baseline.
  • the minimum values at first relief of missing data were symptom-specific.
  • Mean symptom changes in the placebo group were obtained from Tobit analysis, which accounts for the upward bias of changes calculated from observed data only. The probability of unreported symptoms reflecting less relief than the minimum relief of all other patients was combined with the probabilities of the observed symptom values at first relief, to estimate mean changes at first relief of each symptom for the placebo group.
  • Olfactometry The olfactory threshold means of ICX and placebo subjects at baseline and end of study are summarized in Table 4.
  • a negative change indicates improved olfaction.
  • Baseline defined as data collected during visit 2 pre-drug differences between groups were not significantly different (p>.05).
  • Mean changes from baseline to end of study were not significantly different between ICX72 and placebo groups (p>.05).
  • End of study means were significantly different between ICX72 (7.7) and placebo (6.0) (p ⁇ .05).
  • There were no significant differences between baseline or the change from baseline to end of study olfactory threshold means for ICX and placebo subjects (p>.05).
  • ICX subjects had significantly higher olfactory threshold means compared to placebo at visit 3 (p ⁇ .05) indicating that their sense of smell was actually improved during the end of study visit compared to placebo.
  • ICX provides a rapid onset of relief for rhinitis subjects with a non-allergic component, while also providing safe, sustained relief over the course of the two week treatment period.
  • the headache relief composition provides relief of symptoms such as migraines, general headaches, tension, chronic and occasional headaches, and dizziness, and visual distortions associated with headaches.
  • the headache relief composition comprises capsicum
  • An embodiment may comprise potassium sorbate at a concentration of about 0.05% to about 0.30% w/w.
  • the eucalyptol is used to ameliorate the sensory experience and soothe the nasal mucosa.
  • the peppermint oil relieves and helps prevent headache symptoms.
  • the rosemary extract is an anti-microbial agent and a natural preservative which protects and stabilizes the headache relief composition. In a surprising and unexpected result, the rosemary extract was also found to make the sensory experience due to the presence of capsicum in the composition more tolerable to the user, without negatively affecting the efficacy of the composition.
  • the vegetable glycerin is a moisturizer, assists the capsaicinoids contained in the capsicum to maintain its potency and effectiveness for longer periods of time, shortens the length of time of the burning sensation associated with the capsaicinoids in the capsicum without reducing its effectiveness, and stabilizes the formula.
  • the ascorbic acid adjusts the pH supports the immune system, and acts as a natural preservative.
  • the citric acid further adjusts the pH level and stabilizes the formula. Any other suitable pH modulator may be used to adjust and/or maintain the pH of the composition.
  • the sea salt acts as a nasal cavity cleanser which helps flush out bacteria, and dried or clogged mucous which can affect the performance of nerve receptors in the trigeminal region.
  • the headache relief composition may be homeopathic wherein the eucalyptol is used to ameliorate the sensory experience and soothe the nasal mucosa, and the feverfew extract is for headache relief. Furthermore, the headache relief composition may include both eucalyptol and feverfew extract as a tincture. [0094] In still another embodiment of the present invention, the headache relief composition may include between about 0.0044% to 0.0047% by weight of the total water weight of capsicum comprising, but not limited to, capsaicin, dihydrocapsaicin, and nordihydrocapsaicin, or about 0.7 to about 1 .5 ppm total capsaicinoids.
  • One example of the headache relief composition in accordance with an embodiment of the present invention in 5 gallons of purified water includes:
  • the headache relief composition may be administered as a preventative and symptomatic tool.
  • the composition may further comprise from about 0.05% to about 0.30% w/w or about 0.1 2% by weight of the total water weight of potassium sorbate.
  • the allergy relief composition provides relief of symptoms caused by allergies such as nasal congestion, sinus pressure, and
  • the allergy relief composition includes capsicum comprising capsaicin, dihydrocapsaicin, and nordihydrocapsaicin, nettle extract, eucalyptol, rosemary extract, vegetable glycerin, ascorbic acid, citric acid, and sea salt.
  • the nettle extract helps relieve and desensitize allergy symptoms and related allergy triggers.
  • the eucalyptol is used to ameliorate the sensory experience and soothe the nasal mucosa.
  • the rosemary extract is an anti-microbial agent and a natural preservative which protects and stabilizes the allergy relief composition.
  • the rosemary extract was also found to make the sensory experience due to the presence of capsicum in the composition more tolerable to the user, without negatively affecting the efficacy of the composition.
  • the vegetable glycerin is a moisturizer, assists the capsaicinoids contained in the capsicum to maintain their potency and effectiveness for longer periods of time, shortens the length of time of the burning sensation associated with the capsaicinoids in the capsicum without reducing its effectiveness, and stabilizes the formula.
  • the ascorbic acid adjusts the pH level, supports the immune system, and acts as a natural preservative.
  • the citric acid adjusts the pH level and stabilizes the formula. Any other suitable pH modulator may be used to adjust and/or maintain the pH of the composition.
  • the allergy relief composition may be homeopathic wherein the eucalyptol is used to
  • the homeopathic allergy relief composition may include eucalyptol as a tincture and nettle extract as a tincture.
  • the allergy relief composition may include between about 0.0029% to 0.0032% by weight of the total water weight of capsicum comprising capsaicin, dihydrocapsaicin, and nordihydrocapsaicin, providing about 0.4 to about 0.5 ppm total capsaicinoids.
  • Another embodiment of the allergy relief composition in 5 gallons of purified water includes:
  • the allergy relief composition may be administered as a preventative and symptomatic tool.
  • the composition may further comprise potassium sorbate at a concentration of about 0.05% to about 0.30% w/w.
  • the cold relief composition prevents and provides relief of symptoms caused by colds, flu, and poor immune system performance.
  • the cold relief composition comprises capsicum including, but not limited to, capsaicin, dihydrocapsaicin, and nordihydrocapsaicin, echinacea extract, eucalyptol, golden seal extract, spearmint oil, vegetable glycerin, ascorbic acid, citric acid and sea salt.
  • the echinacea extract and the golden seal extract support the immune system.
  • the eucalyptol is used to ameliorate the sensory experience and soothe the nasal mucosa.
  • the spearmint oil provides a sweet taste.
  • the vegetable glycerin is a moisturizer, assists the capsaicinoids contained in the capsicum to maintain its potency and effectiveness for longer periods of time, shortens the length of time of the burning sensation associated with the capsaicinoids in the capsicum without reducing its effectiveness, and stabilizes the formula.
  • the ascorbic acid adjusts the pH level, supports the immune system, and acts as a natural preservative.
  • the citric acid adjusts the pH level and stabilizes the formula. Any other suitable pH modulator may be used to adjust and/or maintain the pH of the composition.
  • the sea salt acts as a natural preservative.
  • the cold relief composition may be homeopathic wherein the eucalyptol is used to ameliorate the sensory experience and soothe the nasal mucosa, and the echinacea extract and golden seal extract provide immune system support.
  • the homeopathic cold relief composition may include eucalyptol as a tincture, echinacea extract as a tincture, and golden seal extract as a tincture.
  • the cold relief composition may comprise between about 0.0024% to 0.0027% by weight of the total water weight of capsicum comprising capsaicin,
  • dihydrocapsaicin, and nordihydrocapsaicin providing about 0.3 to about 0.7 ppm total capsaicinoids.
  • One example of the cold relief composition in accordance with an embodiment of the present invention in 5 gallons of purified water includes:
  • the cold relief composition may be administered before coming into contact with potential germs such as crowded environments, malls, schools, and airplanes.

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Abstract

La présente invention concerne une composition appropriée pour l'administration intranasale et comprenant la capsaïcine, la dihydrocapsaïcine et la nordihydrocapsaïcine sous la forme du capsicum utilisé comme agent thérapeutique.
PCT/US2011/051981 2010-08-03 2011-09-16 Agent thérapeutique pour administration intranasale et son procédé de fabrication et d'utilisation WO2012019204A2 (fr)

Applications Claiming Priority (4)

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US12/849,088 US20100322961A1 (en) 2007-03-30 2010-08-03 Intranasal Drug Delivery System
US12/849,088 2010-08-03
US40539010P 2010-10-21 2010-10-21
US61/405,390 2010-10-21

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US11484580B2 (en) 2014-07-18 2022-11-01 Revance Therapeutics, Inc. Topical ocular preparation of botulinum toxin for use in ocular surface disease

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US20120183624A1 (en) * 2012-03-23 2012-07-19 Forces Of Nature, Inc. Method for manufacturing homeopathic personal care products
US20140056990A1 (en) * 2012-08-24 2014-02-27 Vr1, Inc. Composition for the treatment of migraine headaches and methods thereof

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US11484580B2 (en) 2014-07-18 2022-11-01 Revance Therapeutics, Inc. Topical ocular preparation of botulinum toxin for use in ocular surface disease

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