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WO2000050025A1 - Antidepresseurs tricycliques topiques - Google Patents

Antidepresseurs tricycliques topiques Download PDF

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Publication number
WO2000050025A1
WO2000050025A1 PCT/GB2000/000640 GB0000640W WO0050025A1 WO 2000050025 A1 WO2000050025 A1 WO 2000050025A1 GB 0000640 W GB0000640 W GB 0000640W WO 0050025 A1 WO0050025 A1 WO 0050025A1
Authority
WO
WIPO (PCT)
Prior art keywords
pain
doxepin
tca
compound
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2000/000640
Other languages
English (en)
Inventor
Gary John Mccleane
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bioglan Laboratories Ltd
Original Assignee
Bioglan Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bioglan Laboratories Ltd filed Critical Bioglan Laboratories Ltd
Priority to BR0008402-6A priority Critical patent/BR0008402A/pt
Priority to JP2000600637A priority patent/JP2002537330A/ja
Priority to EP00905198A priority patent/EP1152754A1/fr
Priority to CA002362564A priority patent/CA2362564A1/fr
Priority to IL14451100A priority patent/IL144511A0/xx
Priority to AU26825/00A priority patent/AU2682500A/en
Publication of WO2000050025A1 publication Critical patent/WO2000050025A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of tricyclic antidepressants (TCAs), particularly doxepin, doxepin hydrochloride and its metabolites, as topically applicable analgesics.
  • TCAs tricyclic antidepressants
  • Tricyclic antidepressants are a class of antidepressants which are generally prescribed to individuals suffering from depression and are usually formulated for oral administration. There are at least 28 different compounds which fall under the definition of TCAs (see The Merck Index, 12 th Edition, page "THER-8"). In addition to their use in the treatment of depression, a number of TCAs have also been proven to be effective, when administered orally, in providing an analgesic or pain-relieving effect particularly in the treatment of neuropathic pain [1].
  • Neuropathic pain refers to pain resulting from a disease which affects the function of one or more peripheral nerves.
  • the disease, peripheral neuropathy may be restricted to the peripheral nervous system, involve both the peripheral and central nervous system, or affect multiple organ systems.
  • Peripheral neuropathies can be encountered in all age groups and may be hereditary or acquired, with diverse causes including diabetes, HIV infection and cancer.
  • the resulting pain may be acute (lasting days), sub-acute (weeks) or chronic (months or years) (see Pathology, 2 nd Edition, Rubin & Faber, J.B. Lippincott & Co. 1994)
  • TCAs Pain relieving effect of TCAs, when administered orally, in neuropathic pain, with a broad spectrum of these agents including Amitriptyline [2,3,4,5,8,13,16], Imipramine [11,15], Desipramine [6,7,8,9,12] and Clomipramine [9,10,14].
  • This analgesic effect is independent of their antidepressant properties [2,3] and is not associated with changes in peripheral and autonomic nerve function [9].
  • the effect of TCAs are not replicated by the other classes of antidepressants. There appears to be a relationship between plasma level of the TCA and therapeutic effect [9].
  • TCAs are often complicated by side effects, with such effects being almost as common as therapeutic effect (numbers needed to treat (NNT) for intended effect between 2.3 and 3 depending on condition, NNT for side effects 3.7, [1]).
  • Common side effects experienced with taking these drugs orally include drowsiness, asthenia, increased appetite, dry mouth, diarrhoea, dyspepsia and headache. Patients are therefore often reluctant to take a dose sufficient to achieve substantial pain relief due to the side effects produced. Moreover, such side effects may discourage the use of these compounds in patients requiring long term treatment. Thus, it would be desirable to use TCAs in a formulation in which the therapeutic effects could outweigh the undesirable side effects.
  • Doxepin is a dibenzoxepin derivative and is one TCA belonging to the group of dibenzoxepin tricyclic compounds (see Merck Index, 12 th Edition, compound no. 3492). It is generally produced as an isomeric mixture of both its cis and trans isomers. Its hydrochloride salt, doxepin hydrochloride (1-propanamine, 3- dibenz(b,e)oxepin-ll (6H)ylidene-N,N-dimethyl-, hydrochloride), has a molecular formula C 19 H 21 NO.HCl and a molecular weight of 316.
  • doxepin When taken orally, doxepin is absorbed into the systemic circulation and undergoes hepatic metabolism that results in conversion to a number of metabolites, with the principle active metabolite being desmethyldoxepin.
  • the principle active metabolite being desmethyldoxepin.
  • a number of side effects are seen in patients taking doxepin orally, drowsiness being most commonly observed.
  • doxepin hydrochloride has been formulated as a cream suitable for topical application for use as an antipruritic in conditions such as eczema (eczematous dermatitis, atopic dermatitis and lichen simplex chronicus).
  • eczema eczematous dermatitis, atopic dermatitis and lichen simplex chronicus
  • a 5% cream Xepin cream, available from Bioglan Laboratories, Hitchin, Hertfordshire, England
  • a product licence for relief of pruritis (itching) associated with eczema.
  • the topical cream is indicated for the short-term (up to 8 days) management of moderate pruritis. The exact mechanism by which doxepin exerts its antipruritic effect is unknown.
  • the present invention provides the use of doxepin, doxepin hydrochloride or a metabolite of doxepin or doxepin hydrochloride in the preparation of a medicament for ameliorating pain in an individual.
  • doxepin, doxepin hydrochloride or their metabolites are referred to, it is to be understood to include both the cis and trans isomers of doxepin or doxepin hydrochloride and isomeric mixtures of the same, any other salts of doxepin and their metabolites including the primary active metabolite, desmethyldoxepin.
  • medicaments prepared in accordance with the invention are said to ameliorate or to be for ameliorating pain, it is meant that they are effective to reduce the intensity of pain, or have an analgesic effect, and, although a so described agent is preferably capable of eliminating a particular pain, it need not necessarily be capable of so doing.
  • pain is used in a general sense and is intended to encompass pain levels between the merely uncomfortable and the virtually unbearable.
  • the present invention provides the use of a tricyclic antidepressant or TCA in the preparation of a medicament for ameliorating pain in an individual, wherein the medicament is formulated for topical application.
  • TCA tricyclic antidepressants. This class of compounds includes at least 28 different compounds (see The Merck Index, 12 th Edition, page "THER-8").
  • the TCA is amitriptyline, imipramine, desipramine or clomipramine.
  • the TCA is doxepin, doxepin hydrochloride or their metabolites.
  • the present inventor has demonstrated for the first time an analgesic effect of the topically applied TCA, doxepin, in chronic human neuropathic pain [25].
  • Capsaicin whose use as an analgesic was described as long ago as 1850 [17], has a verified analgesic effect in the pain of post herpetic neuralgia [18,19,20], diabetic neuropathy [21,22] and surgical neuropathic pain [23].
  • Capsaicin my be represented by the general formula I
  • Capsaicin causes release of substance P from C fibre afferent neurones, and repeated application reversibly depletes stores of substance P and therefore reduces pain transmission from peripheral nerve fibres to higher centres [24].
  • doxepin capsaicin
  • capsaicin capsaicin and a doxepin/capsaicin mixture
  • the analgesia with the doxepin/capsaicin mixture was of more rapid onset.
  • the onset of analgesia with doxepin/capsaicin mixtures became apparent in some cases within 1 week of commencing treatment, compared to as much as 2 weeks with doxepin alone.
  • TCA for the manufacture of a medicament for ameliorating deep seated or internal pain or discomfort in an individual, wherein the TCA has an ameliorating effect upon said pain.
  • a pharmaceutical composition comprising a TCA and a compound of formula I:
  • a pharmaceutical composition according to the invention in its fourth aspect for use as an analgesic.
  • the TCA is present in the pharmaceutical composition in an amount sufficient to reduce burning discomfort associated with the application of a compound of formula I to the skin.
  • the compound of formula I is present in an amount sufficient to augment an analgesic effect provided by the TCA.
  • the medicament further comprises a pharmaceutically active carrier rendering it suitable for topical application, preferably to the skin.
  • the medicament is a cream, jelly or ointment.
  • Suitable carriers are well known to those skilled in the art. Suitable carriers include those employed in Xepin cream available from Bioglan Laboratories Ltd. These can include a base cream of pH3.5-5.5 that includes the inactive ingredients: sorbitol, cetyl alcohol, isopropyl myristate, glyceiyl stearate, PEG- 100 stearate, petrolatum, benzyl alcohol, titanium dioxide and purified water.
  • the medicament for use in accordance with the invention is formulated for topical application at or in the vicinity of the source of pain or the perceived origin of the pain (even if, in reality it is more central).
  • patients prefer topical preparations of pain-relieving compounds to oral ones.
  • patients like the notion that they can apply the medication to the site they perceive the pain to be originating from (even if in reality it is more central).
  • a topical preparation By applying a topical preparation, patients would experience less severe side effects to those experienced upon taking the amount of TCA in an oral formulation which would be sufficient to elicit an analgesic effect.
  • a topical preparation can be used over a longer time period and therefore in the treatment of chronic or long lasting pain. Such a preparation would, therefore, be more acceptable to patients requiring long-term treatment.
  • doxepin doxepin hydrochloride or their metabolites in a medicament formulated for topical application, optionally in conjunction with capsaicin or a compound that causes release of substance P from C-fibre afferent neurones, or reversibly depletes stores of substance P, prepared in accordance with the present invention, as an analgesic would not experience the side effects, including drowsiness, which are associated with an oral preparation of doxepin.
  • the medicament prepared in accordance with the present invention is for use in ameliorating pain in an individual suffering from neuropathic pain, preferably chronic neuropathic pain. It is to be understood that such pain is characterised by symptoms including shooting, burning, numbness, paraesthesia/dyaesthesia (tingling) and allodynia. In particular chronic neuropathic pain is characterised by the presence of three of these five associated constituent symptoms.
  • the mean duration of the pain suffered by individuals to be treated is 69 months.
  • the medicament prepared in accordance with the invention can be for long term use. Long term means more than 8 days use of the medicament, and includes treatment of many months duration, if not longer.
  • the use of the medicament prepared in accordance with the current invention is not associated with the significant side effects which are normally associated with oral administration of a TCA. These side effects include drowsiness.
  • the medicament made in accordance with the current invention is for use in individuals who have previously had treatment failure with oral TCAs (either lack of analgesic effect or intolerable side effects).
  • the medicament prepared in accordance with the current invention comprises between 2.5 and 7.5% doxepin hydrochloride but, more preferably, 5% doxepin hydrochloride.
  • the medicament preferably comprises between 0.01 to 0J %, preferably between 0.015 and 0.075%, and, more preferably, between 0.015 and 0.035% capsaicin.
  • the medicament comprises 3J % doxepin and 0.025 % capsaicin.
  • doxepin and doxepin hydrochloride are known compounds, with a history of use in individuals suffering from depression or pruritis.
  • the present invention relates to the use of a known drug, with a well recognised spectra of possible side effects and contraindications, in a new application.
  • Example 1 In a randomised, double blind, placebo controlled study, the effect of twice daily application of doxepin hydrochloride 5% was compared with placebo in forty patients with neuropathic pain. The details of this study are set out in Example 1 below. The results show that there was a significant reduction in pain scores in those treated with topical doxepin hydrochloride when compared to placebo. Minor side effects were seen in 3 patients. There was no significant difference in the drowsiness levels in the two groups.
  • doxepin hydrochloride has an analgesic effect in neuropathic pain and, when applied topically, is not commonly associated with side effects.
  • Randomised, double-blind placebo controlled Patients in each group were instructed to apply a volume of cream equal to the size of a grain of rice to the painful area twice daily over a four week study period. Patients in group A received doxepin, those in group B placebo.
  • neuropathic pain was diagnosed when patients presented with pain which included at least 3 of the constituent symptoms of neuropathic pain, namely shooting pain, burning, numbness, pareasthesiae and sensitivity (allodynia). All patients had pain that was unresponsive to simple or compound codeine containing analgesics or non-steroidal anti-inflammatory drugs. All patients had tried oral TCAs for their pain and had either been unresponsive or intolerant.
  • VAS visual analogue score

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne l'utilisation de la doxépine, d'un hydrochlorure de doxépine ou d'un métabolite de doxépine ou d'un hydrochlorure de doxépine dans la préparation d'un médicament qui permet de soulager une douleur chez un individu.
PCT/GB2000/000640 1999-02-23 2000-02-23 Antidepresseurs tricycliques topiques Ceased WO2000050025A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BR0008402-6A BR0008402A (pt) 1999-02-23 2000-02-23 Usos de doxepina, cloridreto de doxepina ou um metabólito de doxepina ou cloridreto de doxepina, e de um tca, composição farmacêutica, métodos para prover um tratamento analgésico, e para melhorar a dor profunda localizada ou interna
JP2000600637A JP2002537330A (ja) 1999-02-23 2000-02-23 鎮痛剤としての局所用三環系抗うつ剤
EP00905198A EP1152754A1 (fr) 1999-02-23 2000-02-23 Antidepresseurs tricycliques topiques
CA002362564A CA2362564A1 (fr) 1999-02-23 2000-02-23 Antidepresseurs tricycliques topiques
IL14451100A IL144511A0 (en) 1999-02-23 2000-02-23 Topic tricyclic antidepressants as analgesics
AU26825/00A AU2682500A (en) 1999-02-23 2000-02-23 Topic tricyclic antidepressants as analgesics

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9904163.4A GB9904163D0 (en) 1999-02-23 1999-02-23 Pharmaceutical compositions
GB9904163.4 1999-02-23

Publications (1)

Publication Number Publication Date
WO2000050025A1 true WO2000050025A1 (fr) 2000-08-31

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PCT/GB2000/000640 Ceased WO2000050025A1 (fr) 1999-02-23 2000-02-23 Antidepresseurs tricycliques topiques

Country Status (9)

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EP (1) EP1152754A1 (fr)
JP (1) JP2002537330A (fr)
AU (1) AU2682500A (fr)
BR (1) BR0008402A (fr)
CA (1) CA2362564A1 (fr)
GB (1) GB9904163D0 (fr)
HU (1) HUP0200061A2 (fr)
IL (1) IL144511A0 (fr)
WO (1) WO2000050025A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1284151A1 (fr) * 1999-04-12 2003-02-19 Donald A. Rhodes Traitement topique de la douleur et pour améliorer la cicatrisation, qui inclut la capsaicine comme analgésique
WO2007136741A3 (fr) * 2006-05-19 2008-01-24 Somaxon Pharmaceuticals Inc N-desméthyldoxépine et procédés pour traiter les troubles du sommeil l'utilisant
EP1711054A4 (fr) * 2004-02-05 2008-10-15 Rodlen Lab Inc Methode et compositions pour le traitement de troubles douloureux
EP1438020A4 (fr) * 2001-08-17 2010-01-13 Epicept Corp Compositions topiques et methodes de traitement de la douleur
US8367733B2 (en) 2002-12-18 2013-02-05 Vallinex, Inc. Infiltration of capsaicin into surgical sites and open wounds
US8420600B2 (en) 2002-12-18 2013-04-16 Vallinex, Inc. Injectable capsaicin
US20130123295A1 (en) * 2001-06-07 2013-05-16 Analgesic Neuropharmaceuticals, Llc Treatment of neuropathic pain with n-methyl-d-aspartate (nmda) receptor antagonists
US8513299B2 (en) 2006-05-19 2013-08-20 Pernix Sleep, Inc. Methods of using low-dose doxepin for the improvement of sleep
US9463181B2 (en) 2006-05-19 2016-10-11 Pemix Sleep, Inc. Doxepin isomers and isomeric mixtures and methods of using the same to treat sleep disorders
US9498462B2 (en) 2006-05-19 2016-11-22 Pernix Sleep, Inc. Doxepin trans isomers and isomeric mixtures and methods of using the same to treat sleep disorders
US9532971B2 (en) 2007-04-13 2017-01-03 Pernix Sleep, Inc. Low-dose doxepin formulations and methods of making and using the same
US9572814B2 (en) 2006-07-20 2017-02-21 Pernix Sleep, Inc. Methods of improving the pharmacokinetics of doxepin
US9907779B2 (en) 2006-10-25 2018-03-06 Pernix Sleep, Inc. Ultra low dose doxepin and methods of using the same to treat sleep disorders
US11013712B2 (en) 2006-12-06 2021-05-25 Currax Pharmaceuticals Llc Methods of treating insomnia using a combination therapy of low-dose doxepin and zolpidem
US11234954B2 (en) 2006-05-19 2022-02-01 Currax Pharmaceuticals Llc Low-dose doxepin for treatment of sleep disorders in elderly patients

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007049825A1 (fr) * 2005-10-28 2007-05-03 Kyushu University, National University Corporation Antagoniste du recepteur p2x4antagoniste du recepteur p2x4antagoniste du recepteur p2x4

Citations (3)

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Publication number Priority date Publication date Assignee Title
US5008289A (en) * 1988-12-02 1991-04-16 Galenpharma, Inc. Composition for treating nasal disorders and headaches
WO1997010815A1 (fr) * 1995-09-22 1997-03-27 Frome Bruce M Preparation de compositions regionales topiques destinees a soulager la douleur
WO1999059598A1 (fr) * 1998-05-19 1999-11-25 Dalhousie University Utilisation d'antidepresseurs tricycliques pour l'analgesie locale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5008289A (en) * 1988-12-02 1991-04-16 Galenpharma, Inc. Composition for treating nasal disorders and headaches
WO1997010815A1 (fr) * 1995-09-22 1997-03-27 Frome Bruce M Preparation de compositions regionales topiques destinees a soulager la douleur
WO1999059598A1 (fr) * 1998-05-19 1999-11-25 Dalhousie University Utilisation d'antidepresseurs tricycliques pour l'analgesie locale

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BERBERIAN B J ET AL: "The addition of topical doxepin to corticosteroid therapy: an improved treatment regimen for atopic dermatitis.", INTERNATIONAL JOURNAL OF DERMATOLOGY, (1999 FEB) 38 (2) 145-8., XP000909356 *
EMANUELE N.V. ET AL: "Diabetic neuropathy: Therapies for peripheral and autonomic symptoms.", GERIATRICS, (1997) 52/4 (40-50)., XP000090304 *
GALER B.S.: "Neuropathic pain of peripheral origin: Advances in pharmacologic treatment.", NEUROLOGY, (1995) 45/12 SUPPL. 9 (S17-S25)., XP000909402 *
VOLMINK J (REPRINT) ET AL: "TREATMENTS FOR POSTHERPETIC NEURALGIA - A SYSTEMATIC REVIEW OF RANDOMIZED CONTROLLED TRIALS", FAMILY PRACTICE, (FEB 1996) VOL. 13, NO. 1, PP. 84-91. ISSN: 0263-2136., UNIV OXFORD, RADCLIFFE INFIRM, DEPT PUBL HLTH & PRIMARY CARE, GIBSON BLDG, OXFORD OX2 6HE, ENGLAND (Reprint), XP000887093 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1284151A1 (fr) * 1999-04-12 2003-02-19 Donald A. Rhodes Traitement topique de la douleur et pour améliorer la cicatrisation, qui inclut la capsaicine comme analgésique
US20130123295A1 (en) * 2001-06-07 2013-05-16 Analgesic Neuropharmaceuticals, Llc Treatment of neuropathic pain with n-methyl-d-aspartate (nmda) receptor antagonists
EP1438020A4 (fr) * 2001-08-17 2010-01-13 Epicept Corp Compositions topiques et methodes de traitement de la douleur
US8367733B2 (en) 2002-12-18 2013-02-05 Vallinex, Inc. Infiltration of capsaicin into surgical sites and open wounds
US8420600B2 (en) 2002-12-18 2013-04-16 Vallinex, Inc. Injectable capsaicin
EP1711054A4 (fr) * 2004-02-05 2008-10-15 Rodlen Lab Inc Methode et compositions pour le traitement de troubles douloureux
US10238620B2 (en) 2006-05-19 2019-03-26 Pernix Sleep, Inc. Methods of using low-dose doxepin for the improvement of sleep
US10251859B2 (en) 2006-05-19 2019-04-09 Pernix Sleep, Inc. Doxepin isomers and isomeric mixtures and methods of using the same to treat sleep disorders
US9107898B2 (en) 2006-05-19 2015-08-18 Pernix Sleep, Inc. Methods of using low-dose doxepin for the improvement of sleep
US9463181B2 (en) 2006-05-19 2016-10-11 Pemix Sleep, Inc. Doxepin isomers and isomeric mixtures and methods of using the same to treat sleep disorders
US9486437B2 (en) 2006-05-19 2016-11-08 Pernix Sleep, Inc. Methods of using low-dose doxepin for the improvement of sleep
US9498462B2 (en) 2006-05-19 2016-11-22 Pernix Sleep, Inc. Doxepin trans isomers and isomeric mixtures and methods of using the same to treat sleep disorders
US11234954B2 (en) 2006-05-19 2022-02-01 Currax Pharmaceuticals Llc Low-dose doxepin for treatment of sleep disorders in elderly patients
US8513299B2 (en) 2006-05-19 2013-08-20 Pernix Sleep, Inc. Methods of using low-dose doxepin for the improvement of sleep
US9861607B2 (en) 2006-05-19 2018-01-09 Procom One, Inc. Methods of using low-dose doxepin for the improvement of sleep
WO2007136741A3 (fr) * 2006-05-19 2008-01-24 Somaxon Pharmaceuticals Inc N-desméthyldoxépine et procédés pour traiter les troubles du sommeil l'utilisant
US10143676B2 (en) 2006-05-19 2018-12-04 Pernix Sleep, Inc. Doxepin trans isomers and isomeric mixtures and methods of using the same to treat sleep disorders
US9572814B2 (en) 2006-07-20 2017-02-21 Pernix Sleep, Inc. Methods of improving the pharmacokinetics of doxepin
US10653660B2 (en) 2006-07-20 2020-05-19 Currax Pharmaceuticals Llc Methods of improving the pharmacokinetics of doxepin
US9907779B2 (en) 2006-10-25 2018-03-06 Pernix Sleep, Inc. Ultra low dose doxepin and methods of using the same to treat sleep disorders
US10507193B2 (en) 2006-10-25 2019-12-17 Currax Pharmaceuticals Llc Ultra low dose doxepin and methods of using the same to treat sleep disorders
US11013712B2 (en) 2006-12-06 2021-05-25 Currax Pharmaceuticals Llc Methods of treating insomnia using a combination therapy of low-dose doxepin and zolpidem
US9907780B2 (en) 2007-04-13 2018-03-06 Pernix Sleep, Inc. Low-dose doxepin formulations and methods of making and using the same
US11096920B2 (en) 2007-04-13 2021-08-24 Currax Pharmaceuticals Llc Low-dose doxepin formulations and methods of making and using the same
US9532971B2 (en) 2007-04-13 2017-01-03 Pernix Sleep, Inc. Low-dose doxepin formulations and methods of making and using the same

Also Published As

Publication number Publication date
GB9904163D0 (en) 1999-04-14
EP1152754A1 (fr) 2001-11-14
JP2002537330A (ja) 2002-11-05
CA2362564A1 (fr) 2000-08-31
HUP0200061A2 (en) 2002-06-29
BR0008402A (pt) 2002-01-29
IL144511A0 (en) 2002-05-23
AU2682500A (en) 2000-09-14

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