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WO2013130577A2 - Compositions et méthodes pour le traitement de la migraine - Google Patents

Compositions et méthodes pour le traitement de la migraine Download PDF

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Publication number
WO2013130577A2
WO2013130577A2 PCT/US2013/027983 US2013027983W WO2013130577A2 WO 2013130577 A2 WO2013130577 A2 WO 2013130577A2 US 2013027983 W US2013027983 W US 2013027983W WO 2013130577 A2 WO2013130577 A2 WO 2013130577A2
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Prior art keywords
nasal
compositions
treatment
migraine
composition
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PCT/US2013/027983
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English (en)
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WO2013130577A3 (fr
Inventor
Gerald Horn
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Eye Therapies, Llc
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Priority claimed from US13/406,321 external-priority patent/US20120156244A1/en
Application filed by Eye Therapies, Llc filed Critical Eye Therapies, Llc
Priority to JP2014558959A priority Critical patent/JP2015517980A/ja
Priority to CA2865593A priority patent/CA2865593A1/fr
Priority to EP13754567.9A priority patent/EP2819674A2/fr
Publication of WO2013130577A2 publication Critical patent/WO2013130577A2/fr
Publication of WO2013130577A3 publication Critical patent/WO2013130577A3/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • 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
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention provides selective a-2 agonist formulations and their uses for the treatment of migraine, nasal congestion, cerebrovascular disease or systemic conditions, and as delivery vehicles to deliver other active agents to treat systemic or cerebrovascular diseases or conditions,
  • Adrenergic receptors mediate physiological responses to the catecholamines, norepinephrine and epinephrine, and are members of the superfami!y of G protein- coupled receptors having seven transmembrane domains. These receptors, which are divided pharmacologicaliy into aipha-1 (a-1), aipha-2 (a-2) and ⁇ -adrenergic receptor types, are involved in diverse physiological functions including functions of the cardiovascular and central nervous systems.
  • a-1 adrenergic receptors are typically excitatory postsynaptic receptors which generally mediate responses in an effector organ, while a-2 adrenergic receptors are located postsynaptically as well as presynaptically, where they inhibit release of neurotransmitters.
  • the a-adrenergic receptors also mediate vascular constriction. Agonists of a-2 adrenergic receptors are currently used for the treatment of hypertension, glaucoma, spasticity, and attention-deficit disorder, in the suppression of opiate withdrawal, as adjuncts to general anesthesia and in the treatment of cancer pain.
  • a-2 adrenergic receptors are present in various bodily organs, including eyes and nose, it is believed that they play a role in nasal congestion, among many other diseases.
  • a-2 adrenergic receptors are presently classified into three subtypes based on their pharmacological and molecular characterization: a-2A/D (a-2A in human and a-2D in rat); a-2B; and a-2C (Bylund et. al., Pharmacol. Rev. 46:121-136 (1994); and Hein and Kobiika, Neuropharmacol. 34:357-366 (1995)).
  • the a ⁇ 2A, a-2B, and a-2C subtypes appear to regulate arterial and/or venular contraction in some vascular beds, and the a- 2A and a ⁇ 2C subtypes mediate feedback inhibition of norepinephrine release from sympathetic nerve endings.
  • brimonidine which has been used for lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension
  • guanfacine which has been used to control high blood pressure
  • dexmedetomidine which has been used as a sedative, analgesic, sympatholytic and anxiolytic
  • methyl dopa which has been used as a centrally -acting adrenergic antihypertensive
  • Nasal conditions such as nasal congestion, cause inconveniences and sufferings to many patients.
  • the use of conventional decongestant nasal sprays cause rebound congestion often lasting 24 hours or longer which typically results after using these sprays for more than three consecutive days, and often after even a single day use.
  • continued use of conventional nasal decongestants may result in chronic and long term inflammatory pathological conditions. They frequently result as a patient attempts to reverse the rebound congestion with more and more frequent use of the conventional nasal decongestant.
  • Phenylephrine, a strong a-1 agonist, and oxymetazoline, a strong a-1 agonist with some a-2 agonist activity are powerful nasal decongestants. However, they are associated with numerous side effects from repeat use. Rhinitis medicamentosa is one such result of inflammatory ischemic changes from such patterns of use, ultimately resulting in a total nasal blockage which may not be relieved by simply stopping the medication, it may take days, weeks, months, or even medical or surgical intervention to treat rhinitis medicamentosa. It is currently estimated that 10 million U.S. alone suffer from rhinitis medicamentosa.
  • rhinitis medicamentosa inflammatory change
  • rhinitis medicamentosa inflammatory change
  • allergic rhinitis in particular, and nasal congestion in general are common disorders, affecting over 40 million individuais in the U.S. alone with long term and/or chronic treatment need, Some estimate that over $5 billion is spent annually on medications to relieve nasal obstruction, an additional $60 million on surgical remedies, and another $10 billion on the treatment of associated disorders.
  • Karlrnan CP The problem of nasal obstruction. Otolaryngol Clin North Am 1989;22:253-64).
  • nasal congestion and allergic rhinitis Including but not limited to asthma, other upper respiratory conditions, including bronchitis, sinusitis, gastroesophageal reflux, sleep apnea, ear infections, and migraine headaches.
  • migraine headaches It is believed that many perceived sinus headaches are more accurately diagnosed as migraine headaches, and that allergic rhinitis is an associated condition. Patients with a high incidence of positive allergy tests have been found to be predisposed to migraine headaches, and 34% of patients with allergic rhinitis have migraine headaches vs. 4% in those without allergic rhinitis. Thus, allergic rhinitis may increase the frequency of migraine attacks.
  • compositions and methods that would be useful for treatment of nasal conditions, including but not limited to nasal congestion, as well as systemic conditions. It would be especially desired to arrive at compositions and methods which provide long lasting relief with no or only transient rebound (i.e., less than 2 hrs), allowing daily administration for direct nasal benefit, direct centra! nervous system (CNS) benefit, other systemic benefit, and/or administration of a second drug.
  • CNS direct centra! nervous system
  • the present invention provides pharmaceutical compositions which can be used to treat nasal congestion by delivering low concentrations of a subgroup of selective a-2 adrenergic receptor agonists with only transient (i.e., lasting less than one or two hours), or no rebound congestio with repeated use, and without induction of rhinitis medicamentosa.
  • the invention is based, in part, on a surprising discovery that while a-2 agonists are held to be less powerful vasoconstrictors and decongestants than a-1 agonists, the provided super-selective subclass of a-2 agonists at low concentrations produces comparable or greater nasal decongestion than a-1 and general a-agonists
  • the provided compositions can be in the form of a nasal spray or a topical drop (i.e., a liquid drop).
  • compositions and methods can be used for the treatment and/or prophylaxis of migraine.
  • a preferred a-2 adrenergic receptor agonist for the treatment and/or prophylaxis of migraine is dexmedetomidine.
  • Both nasal (e.g., spray) and oral (slow release and fast release) formulations of dexmedetomidine are provided in the invention.
  • the provided compositions can be used as delivery vehicles to deliver medications which currently require injections or other routes of administration.
  • the present invention provides a pharmaceutical composition comprising a highly selective a-2 adrenergic receptor agonist having a binding affinity of 900 fold or greater, and preferably 950 fold for a ⁇ 2 over a-1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said ⁇ 2 adrenergic receptor agonist is present at a concentration from between about 0.001 % and about 0.075% weight by volume, and preferably 0.005% to 0.05% weight by volume.
  • compositions of the invention comprise a mucoadhesive additive.
  • the invention provides a method of delivering an active agent for the treatment of a systemic or cerebrovascular disease or condition comprising administering to a patient in need thereof the pharmaceutical composition of the invention, wherein said nasal spray composition further comprises the active agent.
  • Diseases and conditions that can be treated with the compositions and methods of the present invention include, but are not limited to, allergies; allergic rhinitis; disseminated intravascular coagulation; allergic shock; septic shock; gastro esophageal reflux; ear infection; sinusitis; nasal congestion; migraine; headaches; cervical dystonia; blepharospasm; spasticity; Alzheimer's disease, attention deficit disorder (ADD); depression, memory loss; sleep apnea; diabetes; asthma; transient ischemic cerebrovascular ischemic attacks (TIA's); cerebrovascular accident; degenerative cerebral disorder; pneumonia; acute respiratory distress syndrome (ARDS); acute lung injury (ALI); and infantile bronchiolitis.
  • allergies include, but are not limited to, allergies; allergic rhinitis; disseminated intravascular coagulation; allergic shock; septic shock; gastro esophageal reflux; ear infection; sinusitis; nasal congestion; migraine; headaches; cervical dystonia; blepharospasm; spasti
  • brimonidine encompasses, without limitation, brimonidine salts and othe derivatives, and specifically includes, but is not limited to, brimonidine tartrate, 5- bromo-6- ⁇ 2-imidazolin-2-ylamino)quinoxaline D-tartrate, AlphaganTM (Allergen. Inc.), and UK14304.
  • diexmedetomidine refers to 5-[(1S)-1-(2,3-dimethoylphenyl)ethyl]-1 H- imidazole and encompasses, without limitation, dexmedetomidine salts and other derivatives.
  • treating and “treatment” refer to reversing, alleviating, inhibiting, or slowing the progress of the disease, disorder, or condition to which such terms apply, or one or more symptoms of such disease, disorder, or condition.
  • preventing and prevention refer to prophylactic use to reduce the likelihood of a disease, disorder, or condition to which such term applies, or one or more symptoms of such disease, disorder, or condition. It is not necessary to achieve a 100% likelihood of prevention; it is sufficient to achieve at least a partial effect of reducing the risk of acquiring such disease, disorder, or condition.
  • nasal condition refers to any disease, disorder, or condition which affects and/or involves the nose. This term includes, but is not limited to, such conditions as nasal congestion, diseases and/or conditions associated with swollen nasal turbinates, all types of rhinitis including but not limited to vasomotor rhinitis and allergic rhinitis, sleep apnea, acute or chronic sinusitis, nasal polyposis, and any disease and/or condition associated with nasal discharge.
  • substantially enlargement of nasal turbinates refers to a significant enlargement of nasal turbinates, for example, more than about 50% compared to the baseline level of the patient so that it negatively affects the patient's breathing.
  • compositions and methods which utilize low concentrations of a super-selective subclass of selective a-2 adrenergic receptor agonists for a variety of applications, including at least: 1) treatment of nasal congestion, 2) treatment of migraine; 3) CMS or systemic delivery system for the selected a-2 agonists, and 4 ⁇ a nasal delivery system for other active ingredients to treat a variety of diseases and conditions.
  • the different applications of the invention are described in a greater detail below.
  • the present invention provides pharmaceutical compositions which can be used to treat nasal congestion by delivering low concentrations of 0.075% or less, more preferably 0.05% or less, and still more preferably of 0.035% or less of a super-selective subclass of highly selective a-2 adrenergic receptor agonists of 900 fold or greater, and still more preferably of 950 fold or greater a-2 to a-1 selectivity, with highly effective decongestant activity equal to or greater than that of phenylephrine and/or oxymetazoline (two commercially used alpha-agonists for topical nasal decongestion), and transient (i.e., typically lasting less than one or two hours), if any, rebound congestion without rhinitis medicamentosa.
  • phenylephrine and/or oxymetazoline two commercially used alpha-agonists for topical nasal decongestion
  • transient i.e., typically lasting less than one or two hours
  • the concentration of a-2 agonists is 0.075% or less, and in more preferred embodiments 0.035% or less, wherein all concentration units are weight by volume, unless otherwise noted. It is believed that the provided compositions produce a more effective nasal decongestant activity at these lower concentrations than the decongestant activity of selective a-2 agonists at higher concentrations (for example, than the activity of BHT 920 (8-allyl-2-amino-5 i 6 1 7 1 8-tetrahydro-4H hiazolo-[4,5 ⁇ djazepine) at 1%. (Co . rboz et al, Pulmonary Pharmacology & Therapeutics 21 (2008) 449-454; Mechanism of decongestant activity of ⁇ -2-adr ' enoceptor agonists)).
  • compositions of the invention retain their effectiveness even when used repeatedly, and further, they result in only transient ( ⁇ 2 hrs) or no rebound, and with greatly diminished or eliminated risk of rhinitis medicamentosa. This is especially surprising and unexpected because a strong decongestant activity of the compositions of the invention would have been expected to result in greater rebound congestion with repeat use. The finding of minimal to absent rebound and rhinitis medicamentosa with repeat use of the present invention is, therefore, contrary to decades old unchallenged teachings of the prior art.
  • the present invention thereby provides a means to optimize a-2 nasal decongestion effectiveness for a particular subclass of a-2 agonists of defined "super" selectivity of 900:1 or greater, with surprisingly potent nasal decongestion and iack of ischemia with repeated use.
  • Other a-2 agonists with similar profiles that may be considered for preferred embodiments based on these discoveries include fadolmidine, dexmedetomidine, guanfacine and guanabenz.
  • Other selective a ⁇ 2 agonists may be readiiy synthesized to demonstrate similar or greater a-2 selectivity.
  • A!pha-2a, -2b, or - 2c receptor selectivity is sufficient for purposes of the present invention.
  • compositions for topical delivery which cause minimal and transient (typically limited to at most a few hours, even with repeat use) or no rebound nasal congestion, has a variety of therapeutic benefits, such as:
  • generalized headaches may include various pathologic triggers and manifestations that variably include components of nasal allergy and/or migraine headache, such as vessel dilation, and that may for these or other reasons respond to triggering CNS a-2 receptors.
  • generalized headaches, cluster headaches, and sinus headaches may be treatable to a useful degree by direct administration via nasal delivery of an a-2 agonist.
  • the present invention provides compositions for nasal decongestion comprising a selective a-2 adrenergic receptor agonist having a binding affinity of 900 fold or greater for a-2 over a-1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said a-2 adrenergic receptor agonist is present at a concentration from between about 0.001% and about 0.075% weight by volume and more preferably 0.005% to 0.05% weight by volume.
  • compositions of the invention are in the form of a nasal spray, in another embodiment, the compositions of the invention are in the form of a topical drop, i.e. liquid.
  • the selective a-2 adrenergic receptor agonist is selected from the group consisting of brimonidine, alpha methyl dopa, guanfacine, fadolmidine, dexmedetomidine, (+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1 ,3-dihydro- imidazole-2-thione, 1-[(irnidazoiidin-2-y!)imino]indazoie, and mixtures of these compounds.
  • the selective a-2 adrenergic receptor agonist is dexmedetomidine or brimonidine.
  • the present invention also discovers a concentration range and means of delivery of dexmedetomidine offering effective reduction of migraine headache pain with a U-shaped dose- response curve, where concentrations above or below the range produce reduced effect, as well as a similar but lower concentration range dose- response curve for migraine prophylaxis.
  • dexmedetomidine can be provided as either nasai (e.g., spray) formulations or oral (extended/sustained release and fast/immediate release) formulations for the treatment of migraine.
  • a preferred concentration of dexmedetomidine is between about 0.01 % and about 0.04%; most preferably between about 0.02% and about 0,025%.
  • a preferred concentration of dexmedetomidine is between about 0.003% and about 0.02%; most preferably between about 0.01% and about 0.015%.
  • the concentration of the selective ⁇ -2 adrenergic receptor agonist is between about 0.01% and about 0.075% weight by volume, more preferably, between about 0.015% and about 0.05%, and even more preferably between about 0.020% and 0.035%.
  • the compositions of the invention include one or more mucoadhesive additives
  • the mucoadhesive or combination of mucoadhesive additives are selected from the group consisting of carboxymethylce!lulose (CMC), hydroxypropylcellulose (HPMC) or other cellulose derivatives, carbomers and poloxamers.
  • the mucoadhesive additive is selected from the group consisting of a carbomer and a poloxamer or either in combination with a cellulose derivative like CMC or HPMC.
  • the concentration of poloxamer is between about 0.5% and about 20%; more preferably, between about 5% and about 15%; and even more preferably, between about 8% and about 12%.
  • the concentration of carbomer is between about 0,05% and 0.5% and more preferably 0.1% to 0.4%.
  • the concentration of a cellulose derivative is between 0.1% and 0.5%, and more preferably about 0.3%.
  • additional inactive ingredients may be added, such as polyvinyl alcohol (PVA), chitosan, chondroitin sulfate, xanthan or other gum, chondroitin sulfate, other mucoadhesives and/or viscosity enhancers, or polyethylene glycol (PEG).
  • Preferred poioxamers include, but are not limited ' to, Poioxamer 407 (or its trade name Pluron ' ic® F127 (BASF Corporation)), which can be used with or without a buffer.
  • Preferred carbomers include Carbopol 954 (Lubrizol Corporation) which can be used with or without a buffer.
  • the goal of an effective nasal decongestant is duration of efficacy of several hours, preferably four hours or more, and more preferably 8 hours or more.
  • Formulations with poioxamer concentrations of 2% to 20%, and brimonidine concentration of 0.035% or less offer preferred embodiments with the optimal combination of quick onset, minimal to no dryness, no sedation, and longer duration of effect.
  • compositions of the invention incorporate two or more mucoadhesives, preferably any combination of two from the group consisting of poioxamers, carbomers, methylceiiulose and the derivatives thereof, particularly poioxamer concentrations of about 8% to 16%, hydroxypropylmethyl cellulose (HPMC) concentrations of about 0.1% to 0.5%., brimonidine concentrations of about 0.010% to 0.020%, and with or without polyvinyl alcohol of about 0.1% to about 0.5%.
  • two or more mucoadhesives preferably any combination of two from the group consisting of poioxamers, carbomers, methylceiiulose and the derivatives thereof, particularly poioxamer concentrations of about 8% to 16%, hydroxypropylmethyl cellulose (HPMC) concentrations of about 0.1% to 0.5%.
  • HPMC hydroxypropylmethyl cellulose
  • brimonidine concentrations of about 0.010% to 0.020%
  • polyvinyl alcohol of about 0.1%
  • the invention also provides a method of treating nasal congestion comprising administering to a patient in need thereof a pharmaceutical composition of the present invention.
  • the invention provides a method of treating nasal congestion comprising administering to a patient in need thereof a nasal spray composition comprising a selective a-2 adrenergic receptor agonist having a binding affinity of 950 fold or greater for a-2 over a-1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said a ⁇ 2 adrenergic receptor agonist is present at a concentration from between about 0.001 % and about 0.075% weight by volume.
  • a nasal spray composition comprising a selective a-2 adrenergic receptor agonist having a binding affinity of 950 fold or greater for a-2 over a-1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said a ⁇ 2 adrenergic receptor agonist is present at a concentration from between about 0.001 % and about 0.075% weight by volume.
  • the invention provides a method of treatment of nasal congestion comprising nasally administering to a patient in need thereof a composition of the present invention and further comprising topically administering to said patient a composition of the present invention as an eye drop,
  • the present invention provides compositions and methods for the use as a nasal deliver system to deliver the active ingredient and/or other active ingredients which currently require injections or other routes of administration to treat a variety of diseases and conditions. Therefore, the provided nasal spray compositions result in their more consistent delivery locally or beyond, and can be used as delivery vehicles to deliver other medications.
  • a ⁇ 2 agonists particularly brimonidine and dexmedetomidine
  • have multiple inotropic effects i.e., the force or energy of muscular contractions
  • cellular mechanisms that include systemic, vascular, direct neuroprotective, and indirect neuroprotective therapeutic benefits.
  • sedation due primarily to a-2 receptors at the locus ceraeulus of the brainstem, may occur.
  • some of the specific a-2 agonist mediated inotropic effects include but are not limited to:
  • E K extracellular signal-regulated kinase
  • anxio!ysis and sedation and/or bypass of the blood brain barrier viii) multiple neuroprotective mechanisms, including increased glutamate synthetase levels with breakdown of excitotoxic glutamate; excitatory amino acid - NMDA pathway neuronal apoptosis suppression; reduction in apoptotic protein synthesis and increase in anti-apoptotic protein neuronal synthesis; decreased mictochondrial lysis and reduction in mitochondrial cytochrome P450; reduced infarct ischemia in cerebral, optic nerve, and retina! ganglion cell models; neuroprotective benefits with long term use and suppression of visual field loss in glaucoma.
  • a-2 agonists for the treatment of systemic or CNS diseases or conditions required oral, intramuscular, intra-peritoneal, or intravenous administration, typically resulting in high levels of sedation or other side effects and inconvenience.
  • the delivery of ct ⁇ 2 agonists through nasal administration was problematic due to the high incidence and variability of the nasal congestion in a general population, limiting consistency and predictability of dosing
  • the present invention provides means of nasal decongestion without rebound congestion, allowing daily administration of a ⁇ 2 agonists (optionally, with additional active agents) through nasal delivery so that the drugs can be absorbed systemically or diffuse into the CNS particularly near the upper turbinates via the nasal cribiform plate, thus bypassing the blood brain barrier.
  • the present invention allows for an even more frequent or daily nasal administration of a-2 agonists or additional drugs, while the conventional nasal decongestants may cause rebound congestion and/or rhinitis medicamentosa with repeated use, and therefore, can typically only be used once a day for a period of about three days.
  • Addition of other drugs to the provided formulations of a-2 agonists for nasal administration including but not limited to ketamine, such as for example to reduce N ⁇ ethyl-D-aspartate (NMDA) receptor excitotoxicity may more effectively treat asthma o more particularly, shock (anaphylactic, septic, smoke inhalation, etc.), and may further improve successful treatment of these and other conditions by safer and or more convenient delivery.
  • ketamine such as for example to reduce N ⁇ ethyl-D-aspartate (NMDA) receptor excitotoxicity
  • shock anaphylactic, septic, smoke inhalation, etc.
  • rhinitis medicamentosa and rebound nasal congestion are a-1 derived receptor triggered events. Because the formulations of the present invention do not include a-1 agonists, and are formulated with highly selective a-2 agonists at very low concentrations, the formulations of the present invention have only negligible a-1 activity.
  • rebound is an event extremely sensitive to a-1 receptor recruitment, and that even selective a-2 agonists, when less selective than the a-2 subclass of the present invention may be insufficiently selective and/or at relatively too high concentrations, and may recruit sufficient a ⁇ 1 receptors in sufficiently high numbers to cause rebound congestion.
  • this may be due to profound mucosal and vascular sensitivity to ischemic consequence of stimulation of a-1 receptors they induce via their relative a- 2/a ⁇ 1 selectivity, and co-dependent concentration driven increased a-1 receptor recruitment.
  • compositions can be used for the treatment of allergic rhinitis and other causes of nasal congestion, and/or delivering other active drugs through either nasal spray or topical dro applications virtually free of a-1 effects.
  • Dexmedetomidine in particular, is a preferred a ⁇ 2 agonist for the treatment and/or prevention of migraine.
  • treatment of th allergic rhinitis may reduce the migraine trigger and frequency and/or severity of migraine attacks.
  • delivery of the active ingredient super-selective a-2 agonist to the CNS directly may cause desired CNS reduction in vascular dilatation and or cause alpha 2 induced vasoconstriction and prevent, reduce, or reverse some or all forms of migraine headaches and their sequelae via triggering CNS a-2 receptors.
  • An improved direct CNS drug absorption may be achieved via a single spray per nostril, or increased after onset of decongestant effect via administration of one or more additional sprays per nostril, particularly with inhalation after spray to achieve maximal superior turbinate distribution.
  • Botox injections for the treatment of migraine headaches typically involve about 155 units of Botox® (Allergan) being injected into 31 sites.
  • Intranasal administration via spray or drop with the present invention combines direct systemic and/or CNS benefits of super-selective a-2 agonist absorption along with local rebound-free decongestion with potential absorption of one of several currently injected medications for treatment of migraine.
  • Addition of any second medication may be rendered more effective with the addition of absorptio enhancers well known to experts in the art, including but not limited to beta-cyclodextrin, dimethyi-beta-cyclodextrin, and/or its derivatives; surfactants, including but not limited to laureth-25; mucolytic agents, including but not limited to N-acetyl-l-cysteine (NAC); powder formulations, including but not limited to cellulose derivatives such as microcrystalline cellulose and ethyl cellulose, sodium glycholate and derivatives.
  • absorptio enhancers well known to experts in the art, including but not limited to beta-cyclodextrin, dimethyi-beta-cyclodextrin, and/or its derivatives
  • surfactants including but not limited to laureth-25
  • mucolytic agents including but not limited to N-acetyl-l-cysteine (NAC)
  • powder formulations
  • compositions and methods of the invention may be used to treat shock, which results from microvascular leakage with loss of intravascular volume.
  • Current treatments of shock with vasoconstrictors often cause induced ischemic consequence, inflammatory reaction, and systemic rebound dilatation and leakage.
  • shock may be treated via systemic absorption via nasal administration of a-2 agonists of the present invention.
  • Either a single or multiple sprays may be used to generate desired systemic levels of the super-selective subclass of a-2 agonists of the present invention.
  • a-2 agonists may take place prior to, concurrently, after, or instead of administration of commonly used vasoconstrictors, such as dopamine, epinephrine, norepinephrine and others. Therefore, many forms of shock, including but not limited to, disseminated intravascular coagulation (DIG), anaphylactic shock, septic shock, acute lung injury (AL1) and acute respiratory distress syndrome (ARDS) and other similar pathologic conditions may be more effectively treated with the compositions and methods of the present invention, and may be aided by selection of dexmedetomidine as the super-selective a ⁇ 2 agonist and/or by the addition of second drug, such as ketamine.
  • DIG disseminated intravascular coagulation
  • AL1 acute lung injury
  • ARDS acute respiratory distress syndrome
  • the present invention can be used for the treatment of allergies, !n one embodiment, the treatment is through allergen desensitization which until the present invention requires repeated injection of low dose allergens.
  • the treatment is through allergen desensitization which until the present invention requires repeated injection of low dose allergens.
  • nasal delivery of allergens was difficult or even impossible because of rebound nasal congestion triggered by nasal administration of an allergen.
  • the formulations of the present invention provide nasal decongestion virtually without rebound effect, the present invention allows replacing injection of one or several allergens by their nasal delivery, which may be repeated daily, and eases self- administration of the allergens.
  • the invention facilitates both cerebral non-blood brain barrier delivery and systemic delivery.
  • nasal delivery of medications was limited by mucosal thickness (normally, between 2-4 mm), turbinate patency upon which the distribution of drug is predicated, and the ciliary and vascular leakage of the drug.
  • the present invention facilitates nasal drug delivery in at least the following ways:
  • the provided nasal spray compositions When used as delivery vehicles, the provided nasal spray compositions reduce mechanical barriers to upper aspects of nose and lower aspects of brain and/or systemic absorption by providing nasal mucosal decongestion, which allows for a more accurate and effective lower concentration bolus of medication to be applied. Further, because the nasal spray compositions result in little, if any, rebound congestion, which when found is typically reversed within two hours vs. many days as in prior art, they can be applied daily without experiencing rebound, or even more than one time per day for long periods of time, thus providing lasting nasal decongestant effect. Another advantage of using the provided compositions is that they can limit bleeding when administered prior to an injection to the nasal mucosa. Further, in some embodiments, the provided nasal compositions can be combined with an allergen to provide desensitization effect for the treatment of allergies.
  • the invention allows for delivery of brimonidine via diffusion through nasal sensory nerves and/or arteries/arterioles in the upper turbinates, particularly the region of the cribiform plate directly into the brain without the need to cross the blood brain barrier, as via systemic administration.
  • Many known central nervous system benefits have been found as a result of systemic, oral, intravenous, and/or intraperitoneal administration of a-2 agonists.
  • Some of the medications which can be delivered via nasal administration with the use of the provided compositions include allergy medications, botulinum toxin, including but not limited to onabotuilnumtoxinA (Botox®, Allergan, Inc.); ketorolac tromethamine (Toradol®, Roche Pharmaceuticals); sumatriptan (Imitrex®, G!axoSmithKline Pharmaceuticals); ergotamines, including but not limited to dihydroergotamine ( igranal®, Valeant Pharmaceuticals); sulfonylureas (oral hypoglycemic); immunotherapeutics; IgE suppressors, including but not limited to antihistamines; non- steroidal anti-inflammatory drugs NSA!Ds) including but not limited to indomethacin, ibuprofen, sulindac sulfide, meclofenamic acid, and flurbiprofen; hydroxychloroquine, selective COX-1 or COX-2 inhibitors; insulin and
  • delivering Botox® using the nasal delivery system of the present invention allows to ensure consistent drug delivery and to achieve an appropriate diffusion of the drug into CNS tissue, replacing the need for the multiple subcutaneous injections.
  • the nasal administration of Botox® eliminates the risk of accidental penetration of a vessel during administration of multiple injections. Reconstitution by a physician, and mixing with the nasal spray formulation of the present invention allows for improved CNS delivery of Botox®, and may reduce migraine headache incidence and/or severity.
  • botulinum toxin In addition to Botox®, other commercially available forms of botulinum toxin may be used in the formulations of the present invention.
  • the invention allows for the nasal administration of a drug by combining the drug with a mucosal decongestant which has a non-rebound property (such as a highly selective a-2 agonist), resulting in an improved mucoadherence and retention of the drug.
  • a mucosal decongestant which has a non-rebound property (such as a highly selective a-2 agonist)
  • This unique application system allows for everyday application of a drug with improved consistency of delivery, whether the nasal mucosa is congested or not, and improves cerebral and/or systemic drug absorption.
  • the invention provides a method of delivering an active agent for the treatment of a systemic or cerebrovascular disease or condition comprising administering to a patient in need thereof the nasal spray composition of the invention, wherein said nasal spray composition further comprises the active agent.
  • the invention further provides methods of treating a disease or condition selected from the grou consisting of allergies; allergic rhinitis; gastro esophageal reflux; ear infections, disseminated intravascular coagulation; allergic shock; septic shock; gastro esophageal reflux; ear infection; sinusitis: nasal congestion; migraines; headaches; cervical dystonia; blepharospasm; spasticity; Alzheimer's disease, attention deficit disorder (ADD); depression, memory loss; sleep apnea; diabetes; asthma; transient ischemic cerebrovascular ischemic attacks (TIA's); cerebrovascular accident; degenerative cerebral disorder; pneumonia; acute respiratory distress syndrome
  • a disease or condition selected from the grou consisting of allergies; allergic rhinitis; gastro esophageal reflux; ear infections, disseminated intravascular coagulation; allergic shock; septic shock; gastro esophageal reflux; ear infection; sinusitis: nasal congestion; migraines; headaches; cervical dystonia;
  • ARDS acute lung injury
  • ALI acute lung injury
  • infantile bronchiolitis infantile bronchiolitis
  • the nasal spray compositions may be repeatedly administered to a patient in need thereof, for example, every eight hours, over the course of days, weeks or months, without resulting in a rebound congestion or rhinitis medicamentosa.
  • formulations of the present invention which are suitable for both treatment and/or prevention of nasal congestion, migraine, and/or other disorders, and as delivery system to deliver additional active agents.
  • the present invention provides compositions for nasal decongestion comprising a selective o 2 adrenergic receptor agonist having a binding affinity of 950 fold or greater for a-2 over a-1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said a ⁇ 2 adrenergic receptor agonist is present at a concentration from between about 0.001% and about 0,075% weight by volume.
  • compositions of the invention are in the form of a nasal spray.
  • compositions of the invention are in the form of a topical drop, i.e. liquid.
  • compositions of the invention are in the form of an oral composition, which can be either an immediate/fast release or extended/slow release composition.
  • compositions of the present invention can be included in a pharmaceutically suitable vehicle suitable for oral ingestion.
  • suitable pharmaceutically acceptable carriers inciude solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound is present in such pharmaceutical compositions in an amount sufficient to provide the desired effect. It is expected that such oral formulations would also be effective for the treatment of anxio!ysis.
  • compositions contemplated for use in the practice of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more of the active ingredients in admixture with an organic or inorganic carrier or excipient suitable for nasal, enteral, or parenteral applications.
  • the active ingredients may be combined, for example, with the usual non-toxic, pharmaceutically and physiologically acceptable carriers for tablets, pellets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, suppositories, solutions, emulsions, suspensions, hard or soft capsules, capiets or syrups or elixirs and any other form suitable for use.
  • the usual non-toxic, pharmaceutically and physiologically acceptable carriers for tablets, pellets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, suppositories, solutions, emulsions, suspensions, hard or soft capsules, capiets or syrups or elixirs and any other form suitable for use.
  • the possible carriers include glucose, lactose, gum acacia, gelatin, mannitoL starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. Sn addition auxiliary, stabilizing, thickening and coloring agents may be used.
  • the selective ot ⁇ 2 adrenergic receptor agonist is selected from the group consisting of brimonidine, alpha methyl dopa, guanfacine, fadolmidine, dexmedetomidine, (+)-(S)-4-[1 ⁇ (2,3 ⁇ dimethy!-phenyl)-ethyl3-1 : 3-dihydro- imidazoie-2-thione, 1-[(imidazolidin-2 ⁇ yl)imino]indazole, and mixtures of these compounds.
  • the selective a-2 adrenergic receptor agonist is dexmedetomidine or brimonidine.
  • the concentration of the selective a-2 adrenergic receptor agonist is between about 0.01% and about 0.075% weight by volume, and even more preferably, between about 0.010% and about 0.035%.
  • compositions of the invention inciude one or more mucoadhesive additives
  • the mucoadhesive additive is selected from the group consisting of carboxymethyicellulose (CMC),
  • the mucoadhesive additive is selected from the group consisting of a carborner and a poloxamer or cellulose derivatives and a poloxamer.
  • the concentration of the poioxamer mucoadhesive additive is between about 0.5% and about 20%; more preferably, between about 5% and about 18%; and even more preferably, between about 8% and about 14%,
  • the concentration of the carborner mucoadhesive additive is between about 0.05% and about 0.5%.
  • the concentration of the methyl cellulose derivatives, such as hydroxypropyl methylcellulose (HPMC) is between about 0.05% and about 5%, and more preferably between about 0.1% and about 0.3%.
  • Preferred poioxamers include, but are not limited to, Poloxamer 407 (or its trade name Pluronie® F127),
  • carbomers include, but are not limited to, Carbopol® 954.
  • the concentration of poloxamer is about 12%, and the concentration of b imonidine is about 0.03%. In another preferred embodiment, the concentration of poloxamer is about 18%, and the concentration of brimonidine is about 0.025%. In another preferred embodiment, the concentration of poloxamer is about 8% and the concentration of brimonidine is about 0.035%. In another preferred embodiment
  • the concentration of carborner without poloxamer is about 0.2%, the pH is between 6.0 and 7.5, and the concentration of brimonidine is about 0.035%.
  • compositions of the invention may be administered as slow release gels, combining any two or all three of poloxamer, carborner, and methylcellulose.
  • brimonidine at 0.033% is combined with Carbopol® 954 (manufactured by Lubrizoi Corporation) at 0.1% and either HPMC at 0.3%, or poloxamer at 1 % to 20%, more preferabl about 10%, or both.
  • polyvinyl alcohol (PVA) at 0.1% to 1%, and more preferably at 0.2% to 0.5%, and still more preferably, at 0.25% to 0.35% may be added.
  • the invention provides a nasal spray composition comprising dexmedetomidine, wherein said dexmedetomidine is at a concentration from between about 0.001% and about 0.05%.
  • a pH of the nasal spray composition is between about 4.0 and about 7.5; more preferably, between about 4.0 and about 6.0; and most preferably between 4.5 and 5.0.
  • compositions of the invention may optionally comprise one or more of the following ingredients or mixtures thereof: Plasdone® K- 29/32, citric acid, polysorbate 80, benzyl alcohol, propylene glycol, polyethylene glycol, microcrystaliine cellulose, camphor, eucalypto!, potassium sorbate, sodium chloride and/or sterile water.
  • An expert in the art may combine or modify the inactive ingredients listed or other inactive ingredients well known to those in the art for nasal formulations, within the concentration range for preferred super-selective a-2 agonist embodiments of the present invention to optimize preferred subjective criteria, such as comfort, and no to slight "menthol-like" sharp sensation on instillation (less than stinging); as well as objective criteria, such as onset, duration, magnitude, no or transient rebound.
  • Plasdone® K-29/32 2%; citric acid: 0.15%; polysorbate 80: 0.75%; benzyl alcohol: 0.5%; propylene glycol: 0.2-2%; polyethylene glycol (PEG); 2%; microcrystaliine cellulose: 2% camphor and/or eucalyptol: 0.01%; potassium sorbate: 0.15%; and sodium chloride: 0.9%.
  • a minimum of four hours of effect is desired, more preferably, six hours, and still more preferably, eight hours or more, ⁇ /ithouf rebound.
  • Virtually all formulations of the present invention provide four or more hours of effective action, and several formulations provide six or more hours. Still other preferred embodiments approach eight hours.
  • Table 2 lists the formulations of the invention which are most preferred for use as nasal decongestants and/or as delivery systems: Table 2
  • PVP polyvinylpyrrolidone
  • P-80 is polysorbate 80
  • PG is propylene giycol
  • CA citric acid
  • BA is benzyl alcohol.
  • concentrations of various ingredients are as follows:
  • Citric Acid USP Anhydrous fine granular 0.0225 gm
  • the final brimonidine concentration is 0.035%, and the final poloxamer concentration is 8%.
  • concentrations of various ingredients are as follows:
  • the invention provides 15ml Nasal Spray Brimonidine Tartrate 0,15% Ophthalmic Solution 3,0 ml
  • the invention provides:
  • NX025WC1 PVA3HPMC3 the invention provides:
  • NX033P 11 WC 1 PVA3H PMC3 the invention provides:
  • Poloxamer 407 11.2% (8 to 11 %)
  • Citric Acid USP Anhydrous fine granular 0.0225 gm
  • Citric Acid USP Anhydrous fine granular 0.0225 gm
  • Citric Acid USP Anhydrous fine granular 0.0225 gm
  • Poloxamer 407 20% 7.5 ml
  • Citric Acid USP Anhydrous fine granular 0.0225 gm
  • Poloxamer 407 20% diluted 10%
  • Citric Acid USP Anhydrous fine granular 0.0225 gm
  • Poloxamer 407 20% diluted 10%
  • Poloxamer 407 25% gel used to create the provided formulations is as follows;
  • Camphor/Eucalyptol mix is as follows:
  • compositions of the invention may also comprise a solubility stabilizer which preferably contains an anionic component, such as peroxide class preservatives.
  • the solubility stabilizer allows one to achieve greater penetration of lipophilic membranes, such as those present at the vascular endothelial surface, in a preferred embodiment, the solubility stabilizer comprises a stabilized oxychloro complex, chlorite, and sodium perborate.
  • Other additives such as ethylenediaminetetraacetic acid (EDTA) or citric acid, may be used where increased mucosal penetration is desired.
  • EDTA ethylenediaminetetraacetic acid
  • potassium sorbate may be used as a preservative to replace benzaikonium chloride (BAK), with known rebound inducing toxicity, or the formulations may be delivered in disposable unit dose nasal spray delivery devices.
  • compositions of the present invention may comprise nitrous oxide inhibitors.
  • the nitrous oxide inhibitors are selected from the group consisting of L-NA E (L-N G -Nitroarginine methyl ester), L- NIL (N6 ⁇ (1-Jminoethyl) ⁇ L-lysine dihydrochloride), L-NIO (N5-(1-lminoethyl)-L-ornithine dihydrochloride), and L-canavine, or combinations thereof.
  • concentration of the nitrous oxide inhibitors is between about 0.005% and about 0.5% weight by volume.
  • compositions of the invention may also include additional components, which include, but are not limited to, preservatives, delivery vehicles, tonicity adjustors, buffers, pH adjustors, antioxidants, and water.
  • the preservatives include, but are not limited to, potassium sorbate, peroxide and peroxide derivatives, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, or phenylmercuric nitrate. Of these, potassium sorbate is used in preferred embodiments.
  • Vehicles useful in a topical composition include, but are not limited to, polyvinyl alcohol, glycerin, povidone, hydroxy propyl methyl cellulose, poioxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water, ft is also possible to use sterile water or a physiological saline solution as a major vehicle.
  • a tonicity adjuster also can be included, if desired, in a topical composition of the invention.
  • a tonicity adjuster can be, without limitation, a salt such as sodium chloride, potassium chloride, mannitoi or glycerin, or another pharmaceutically or ophthalmically acceptable tonicity adjuster.
  • отно ⁇ buffers and means for adjusting pH can be used to prepare topical compositions of the invention.
  • Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers. It is understood that acids or bases can be used to adjust the pH of the composition as needed.
  • Topically acceptable antioxidants useful in preparing a topical composition include, yet are not limited to, sodium metabisulfite, sodium thiosuifate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • the provided composition is an aerosolized composition. It is within a skill in the art to prepare aerosolized compositions of the present invention.
  • the aerosolized compositions of the present invention are generally delivered via an inhaler, jet nebulizer, or ultrasonic nebulizer which is able to produce aerosol particles with size of between about 1 and 10 pm.
  • To make the topical compositions of the present invention one can simply dilute, using methods known in the art, more concentrated solutions of selective ct-2 agonists. The precise method of carrying out the dilutions is not critical. Any commoniy used diluents, including preservatives described above in the application, suitable for topical solutions can be used. Addition of poloxamer may be performed by initially dissolving using cold technique and overnight refrigeration well, known to experts in the art.
  • compositions of the present invention are concentration- dependent. To determine the specific dose for a particuiar patient, a skilled artisan would have to take into account kinetics and absorption characteristics of the particular highly selective a-2 adrenergic receptor agonist.
  • ELDB2P3 formulation was created as follows:
  • P!asdone® PVP k29-32
  • citric acid microcrystalline cellulose
  • potassium sorbate were dissolved in 45 ml of preserved NaCI irrigation.
  • polysorbate 80, benzyl alcohol, propylene glycol, and camphor-eucalypto! mix were added, Poloxamer 407 was stirred in for at least one hour, and refrigerated overnight to totally dissolve. Then, th active ingredient (brimonidine 0.05%) was added.
  • the resultant formulation had no undesirable aftertaste and no stinging. It provided an almost immediate onset of less than 10 seconds. It created a long duration high magnitude decongestant effect without pharyngeal dryness. As there is no preservative, and the pH (about 4.5) is highly acidic, it is believed that the formulation can be used regularly without the rebound congestion.
  • Example 2
  • compositions of the invention were tested.
  • the first formulation, NX040P2 included brimonidine at 0.040% and poloxamer at 2%
  • second formulation included brimonidine at 0.05% and poloxamer at 4%
  • NX050P4 but not NX04QP2 resulted in about two hours of post-instillation nasal congestion after about 8 hours of effect.
  • a range of combinations of brimonidine with various mucoadhesives and inactive ingredient combinations were studied for 1 ⁇ onset of nasal decongestion on a 1 (least) to 4 (most) scale; 2) magnitude of decongestion of turbinates (1-4);
  • Avicel® (manufactured by FMC Corporation) Is a microcrystalline cellulose
  • PVP is polyvinylpyrrolidone (Plasdone®, manufactured by International Specialty Products) R29-32;
  • poiySO is polysorbate 80
  • PEG is polyethylene glycol
  • PG is propylene glycol
  • the main purpose of this experiment was to determine whether ophthalmic coadministration of brimonidine 0.025% increases the duration of the effect of nasal administration of a preferred composition of the present invention.
  • the experiment was to determine whether multiple consecutive (1-3 hours apart) instillations of the compositions of the invention for about 48 hours cause any rebound congestion.
  • a preferred composition of the invention NX020P15PVA3HPMC3, was administered nasally, with repeat administration 1-3 hours after return to baseline five consecutive times. On the third and fifth instillation, ophthalmic dosing was added.
  • Co-administration of the active ingredient of the present invention via ophthalmic and nasal delivery (3 rd and 5 th nasal instillations) vs. nasal delivery alone (1 st , 2 nd , and 4 th instillations) resulted in a substantial increased duration of action to a mean of about 1 .37 hours vs. about 7.39 hours for nasal dosing alone.
  • compositions of the present invention can be used for migraine treatment and/or prophylaxis
  • An individual with migraine headache, with or without aura desires migraine treatment.
  • Aura refers to physical symptoms that precede the headache including visual, visceral, or other sense driven manifestations.
  • the most effective treatment occurs if the preferred dosing of the present invention is administered as early in the aura phase as possible.

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Abstract

L'invention concerne des compositions pharmaceutiques pour le traitement d'une congestion nasale ou d'une migraine, les compositions pharmaceutiques comprenant de faibles concentrations d'une sous classe super-sélective d'agonistes sélectifs du récepteur α-2 adrénergique.
PCT/US2013/027983 2012-02-27 2013-02-27 Compositions et méthodes pour le traitement de la migraine WO2013130577A2 (fr)

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CA2865593A1 (fr) 2013-09-06
JP2015517980A (ja) 2015-06-25
EP2819674A2 (fr) 2015-01-07

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