WO1995005179A1 - Combinaison therapeutique contenant un compose contre le virus zosterien de la varicelle ainsi que de la lamotrigine - Google Patents

Combinaison therapeutique contenant un compose contre le virus zosterien de la varicelle ainsi que de la lamotrigine Download PDF

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Publication number
WO1995005179A1
WO1995005179A1 PCT/GB1994/001800 GB9401800W WO9505179A1 WO 1995005179 A1 WO1995005179 A1 WO 1995005179A1 GB 9401800 W GB9401800 W GB 9401800W WO 9505179 A1 WO9505179 A1 WO 9505179A1
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WO
WIPO (PCT)
Prior art keywords
lamotrigine
combination product
valaciclovir
day
pain
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/GB1994/001800
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English (en)
Inventor
Dorothy Jane Martin Purifoy
Anthony Paul Fiddian
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.)
Wellcome Foundation Ltd
Original Assignee
Wellcome Foundation 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 Wellcome Foundation Ltd filed Critical Wellcome Foundation Ltd
Priority to AU73897/94A priority Critical patent/AU7389794A/en
Publication of WO1995005179A1 publication Critical patent/WO1995005179A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • Therapeutic combination containing an anti-varicel la zoster vi rus compound and la otrigine.
  • This invention relates to the therapeutic combination of an anti-varicella zoster virus (VZV) compound and 3,5-diamino-6-(2,3,-dichlorophenyl)-l,2,4-triazine (hereinafter referred to as lamotrigine) or a pharmaceutically acceptable acid addition salt thereof.
  • VZV anti-varicella zoster virus
  • lamotrigine 3,5-diamino-6-(2,3,-dichlorophenyl)-l,2,4-triazine
  • Post-herpetic neuralgia is a common and debilitating complication of shingles (herpes zoster) which particularly affects the elderly.
  • VZV is the aetiological agent for shingles which is characterised by an acute dermatomal rash and skin crusting with associated " acute pain. In many cases this acute pain is followed by PHN which has been defined as pain that persists (such as after 1 month) in the affected dermatomes after the disappearance of skin crusts.
  • the neuralgia can vary from lightning-like stabbing pain to constant itching or burning pain with hyperesthesia. It can persist for many months or even years and is often refractory to traditional analgesic therapy.
  • lamotrigine was suggested as an analgesic for the treatment of some chronic pain conditions.
  • Other abstracts relating to the use of lamotrigine as an analgesic are as follows:-
  • lamotrigine can be advantageously employed in combination with an anti-VZV compound to provide a therapeutic combination that can be used to treat or prevent VZV infection with the additional benefit of relieving or preventing the pain associated with such infection.
  • the use of lamotrigine in combination with an anti-VZV compound enables one to prevent or reduce the onset of PHN.
  • a combination product comprising an anti-VZV compound and lamotrigine or a pharmaceutically acceptable acid addition salt thereof.
  • the components of the combination may be administered simultaneously, either in the same or different pharmaceutical formulations, or sequentially such that the desired combined effect is achieved, i.e. the lamotrigine provides a prophylactic effect against the onset of PHN associated with the VZV infection, or relieving PHN if it does become established.
  • Relieving PHN includes any one or all of the following:
  • Reference to PHN also includes allodynia.
  • a combination product comprising an anti-VZV compound and lamotrigine or a pharmaceutically acceptable acid addition salt thereof as a combined preparation for simultaneous, separate or sequential use to prevent the onset of or relieve PHN.
  • the present invention further provides a method of treating a VZV infection and preventing or relieving any subsequent PHN (or reducing any other adverse neurological consequences of the VZV infection) in a human which comprises combined, simultaneous, separate or sequential administration to the human subject of an effective anti-VZV amount of an anti- VZV compound and an effective amount of lamotrigine or a pharmaceutically acceptable acid addition salt thereof.
  • the combination should ideally be given as soon as shingles is diagnosed, and no later than the end of the acute phase.
  • acid addition salts of lamotrigine include those formed from hydrochloric, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic, ethanesulphonic, benzenesulphonic oxaloacetic and isethionic acids.
  • the salts of isethionic acid are preferred since they possess particularly good solubility.
  • Lamotrigine can be employed in a dosage range as follows: 25 to 400mg/day, 50 to 400mg/day, 50 to 200mg/ day, 100 to 400mg/day, 200 to 400mg/day and about 300mg/day.
  • the lamotrigine (and the anti-VZV compound) will be taken over at least about a 7 day period.
  • the daily dosage may be constant (e.g. 300mg/day) or may increase over the period of administration (e.g. lOOmg on day 1 increasing to 400mg on day 7).
  • the above dosages and those shown below are those for an adult humans of average weight.
  • the dosage will be calculated on the above amounts of the parent compound.
  • the anti-VZV compound and lamotrigine will generally be employed in a molar ratio of 1:20 to 30:1, preferably 6:1 to 30:1.
  • the anti-VZV compound is preferably valaciclovir (described in European patent specification no. 308065; U.S. No. 4957924) and is employed at 2000 to 4000mg/day, preferably about 3000mg/day.
  • the lamotrigine and anti-VZV compound may be independently administered once, twice or three times daily (such as for valaciclovir) or up to five times daily (such as for acyclovir).
  • the anti-VZV compound valaciclovir is particularly advantageous for use in conjunction with lamotrigine since the dosage of the two compounds are such that they can be readily incorporated in a single unitary oral formulation such as a tablet or a capsule for example containing 250 to 1000 mg of valaciclovir and 25 to 400 mg of lamotrigine, preferably 500 to 1000 mg of valaciclovir and 50 to 300 mg (or 50 to 200 mg) of lamotrigine.
  • a suitable dosage regime would be, for example, two tablets each containing 500mg valaciclovir and 25mg or 50mg lamotrigine administered 3 times daily for seven days; or a molar ratio of valaciclovir to lamotrigine of about 2:1 to 7:1.
  • the components of the combination can be administered as a unitary (such as a combined tablet or capsule formulation) or separate formulations, e.g. where the anti-VZV compound and lamotrigine are administered sequentially as separate tablets but packaged together in a daily dosage blister-pack.
  • the components of the combination can therefore be administered simultaneously; either in the same or different pharmaceutical formulations, or sequentially such that the described combined effect in vivo is achieved, i.e. a novel prophylactic effect preventing the onset of PHN (thereby preventing it becoming established), or relieving the PHN if it does become established.
  • compositions contain one or both of the anti-VZV or lamotrigine components according to the invention together with at least one pharmaceutical carrier or excipient. Such formulations may be prepared in conventional manner.
  • Formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. Formulations for oral administration are especially preferred.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • Oral formulations may further include other agents conventional in the art, such as sweeteners, flavouring agents and thickeners.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient.
  • formulations for oral administration are advantageously presented in the form of water dispersible tablets each containing one or both of the two components of the combination according to the invention.
  • Such water-dispersible tablets can be dispersed in water to provide an aqueous dispersion of the relevant compound(s), which may be advantageous in those situations where it may be difficult for the patient to swallow the tablet.
  • An especially advantageous water-dispersible tablet formulation containing acyclovir or lamotrigine is described in PCT Patent Specification No. WO92/13527. The disclosure of the above PCT Patent Specification is also incorporated herein by reference.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof of an active ingredient.
  • Valaciclovir 500.0 b) Lamotrigine 50.0 c) Lactose 110.0 d) Avicel PH101 110.0 e) Pre-gelled starch 56.0 f) Explotab 42.0 g) Magnesium stearate 7.0
  • Valaciclovir 500.0 b) Lamotrigine 25.0 c) Lactose 50.0 d) Avicel PH101 50.0 e) Pre-gelled starch 28.0 f) Explotab 31.0 g) Magnesium stearate 3.5
  • Valaciclovir 500.0 b) Lamotrigine 25.0 c) Lactose 110.0 d) Avicel PH101 110.0 e) Pre-gelled starch 56.0 f) Explotab 42.0 g) Magnesium stearate 7.0
  • Valaciclovir 1000.0 Lamotrigine 100.0 d) Avicel PH101 120.0 f) Explotab 50.0 g) Magnesium stearate 6.5
  • Figure 1 shows the effect of a single pre-dose of lamotrigine (50mg/kg p.o) on the development of neuropathic pain due to loose ligation on the sciatic nerve in rats, (significance of the difference between columns by Student t test ***p ⁇ 0.001).
  • a first group of six male wistar-strain rats (control group) weighing 200-270g were given 2.0ml/kg methylcellulose (Celacol) and were then anaesthetised by inhalation using isofluorane. An incision was made mid thigh in the right hind limb using asceptic techniques and the muscle blunt dissected to expose the common sciatic nerve. Four ligatures at 1mm apart were tied loosely around the nerve to touch but not constrict it. The wound was then sutured and the animals allowed to recover. Seven days after surgery, hyperalgesia reaction time to paw pressure) was measured in both limbs by applying a constant pressure of 40mm Hg to the paw until a withdrawal response was seen.
  • a second group of six male wister-strain rats (200-270g) were then taken, but firstly given a single pre-dose of lamotrigine (50mg/kg p.o) in 0.25% methylcellulose (Celacol) 1 hour prior to induction of anaesthesia.
  • the sciatic nerve was then ligated as before and the reaction time for each of the control group and the pre-dosed lamotrigine group noted on Figure 1. Mean reaction times for non-ligated (normal) rats were also noted.
  • the reaction times to paw pressure for the normal rats was between 20 and 28 second(s) and in the ligated control rats.
  • valaciclovir and lamotrigine in combination are thus particularly preferred to prevent the onset or relieve PHN.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un produit comprenant un composé contre le virus zostérien de la varicelle ainsi que de la lamotrigine, ce produit se présentant sous la forme d'une préparation combinée à usage séquentiel, séparé ou simultané dans la prévention de l'apparition des algies post-zostériennes ou pour soulager celles-ci si elles s'établissaient.
PCT/GB1994/001800 1993-08-18 1994-08-17 Combinaison therapeutique contenant un compose contre le virus zosterien de la varicelle ainsi que de la lamotrigine Ceased WO1995005179A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU73897/94A AU7389794A (en) 1993-08-18 1994-08-17 Therapeutic combination containing an anti-varicella zoster virus compound and lamotrigine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939317146A GB9317146D0 (en) 1993-08-18 1993-08-18 Therapeutic combinations
GB9317146.0 1993-08-18

Publications (1)

Publication Number Publication Date
WO1995005179A1 true WO1995005179A1 (fr) 1995-02-23

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PCT/GB1994/001800 Ceased WO1995005179A1 (fr) 1993-08-18 1994-08-17 Combinaison therapeutique contenant un compose contre le virus zosterien de la varicelle ainsi que de la lamotrigine

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Country Link
AU (1) AU7389794A (fr)
GB (1) GB9317146D0 (fr)
IL (1) IL110690A0 (fr)
WO (1) WO1995005179A1 (fr)
ZA (1) ZA946217B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000681A1 (fr) * 1995-06-23 1997-01-09 The Wellcome Foundation Limited Composition pharmaceutique contenant de la lamotrigine
WO2004103340A1 (fr) * 2003-05-20 2004-12-02 Ranbaxy Laboratories Limited Comprimes hydrodispersibles a base de lamotrigine
WO2005051350A3 (fr) * 2003-10-28 2005-08-18 Torrent Pharmaceuticals Ltd Comprime dispersible dans l'eau
CN1313081C (zh) * 1995-01-20 2007-05-02 惠尔康基金会集团公司 含有胶体二氧化硅的缬无环鸟苷片剂
EP3797764A1 (fr) * 2019-09-27 2021-03-31 Janusz Chupty Contissi Composition pharmacologique pour le traitement du dysfonctionnement des tissus nerveux, en particulier la latence virale, et utilisation de substances du groupe j05 atc pour le traitement du dysfonctionnement des tissus nerveux, en particulier la latence virale

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0021121A1 (fr) * 1979-06-01 1981-01-07 The Wellcome Foundation Limited Dérivés de la triazine-1,2,4, procédé pour la préparation de tels composés et compositions pharmaceutiques les contenant
EP0308065A2 (fr) * 1987-08-15 1989-03-22 The Wellcome Foundation Limited Nucléosides thérapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0021121A1 (fr) * 1979-06-01 1981-01-07 The Wellcome Foundation Limited Dérivés de la triazine-1,2,4, procédé pour la préparation de tels composés et compositions pharmaceutiques les contenant
EP0308065A2 (fr) * 1987-08-15 1989-03-22 The Wellcome Foundation Limited Nucléosides thérapeutiques

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1313081C (zh) * 1995-01-20 2007-05-02 惠尔康基金会集团公司 含有胶体二氧化硅的缬无环鸟苷片剂
WO1997000681A1 (fr) * 1995-06-23 1997-01-09 The Wellcome Foundation Limited Composition pharmaceutique contenant de la lamotrigine
US5942510A (en) * 1995-06-23 1999-08-24 Glaxo Wellcome Inc. Pharmaceutical composition containing lamotrigine
WO2004103340A1 (fr) * 2003-05-20 2004-12-02 Ranbaxy Laboratories Limited Comprimes hydrodispersibles a base de lamotrigine
WO2005051350A3 (fr) * 2003-10-28 2005-08-18 Torrent Pharmaceuticals Ltd Comprime dispersible dans l'eau
EP3797764A1 (fr) * 2019-09-27 2021-03-31 Janusz Chupty Contissi Composition pharmacologique pour le traitement du dysfonctionnement des tissus nerveux, en particulier la latence virale, et utilisation de substances du groupe j05 atc pour le traitement du dysfonctionnement des tissus nerveux, en particulier la latence virale
WO2021060998A1 (fr) * 2019-09-27 2021-04-01 CHUPTYŚ CONTISSI, Janusz Composition pharmacologique pour le traitement d'un dysfonctionnement du tissu nerveux, en particulier d'une latence virale, et utilisation de substances du groupe j05 atc dans le traitement d'un dysfonctionnement du tissu nerveux, en particulier d'une latence virale

Also Published As

Publication number Publication date
GB9317146D0 (en) 1993-10-06
ZA946217B (en) 1996-02-19
IL110690A0 (en) 1994-11-11
AU7389794A (en) 1995-03-14

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